<PAGE>   1


    As filed with the Securities and Exchange Commission on February 18, 2000
                                                    Registration No. 333-
                                                                         -----
===============================================================================

                       SECURITIES AND EXCHANGE COMMISSION
                             WASHINGTON, D.C. 20549

                          ----------------------------
                                    FORM S-8
                             REGISTRATION STATEMENT
                                      UNDER
                           THE SECURITIES ACT OF 1933

                          GUILFORD PHARMACEUTICALS INC.
             (EXACT NAME OF REGISTRANT AS SPECIFIED IN ITS CHARTER)

<TABLE>

<S>                                              <C>                                                      <C>
DELAWARE                                                                                                       52-1841960
(State or other jurisdiction of                      6611 TRIBUTARY STREET                                  (I.R.S. Employer
Incorporation or organization)                      BALTIMORE, MARYLAND 21224                             Identification  Number)
                                            (Address of principal executive offices)(Zip code)
</TABLE>

              1998 EMPLOYEE SHARE OPTION AND RESTRICTED SHARE PLAN
                            (FULL TITLE OF THE PLAN)

                              CRAIG R. SMITH, M.D.
          CHIEF EXECUTIVE OFFICER, PRESIDENT AND CHAIRMAN OF THE BOARD
                          GUILFORD PHARMACEUTICALS INC.
                              6611 TRIBUTARY STREET
                            BALTIMORE, MARYLAND 21224
                     (NAME AND ADDRESS OF AGENT FOR SERVICE)



                                 (410) 631-6300
          (TELEPHONE NUMBER, INCLUDING AREA CODE, OF AGENT FOR SERVICE)

 ------------------------------------------------------------------------------
                                 WITH A COPY TO:
                             MICHAEL J. SILVER, ESQ.
                             HOGAN & HARTSON L.L.P.
                            111 SOUTH CALVERT STREET
                            BALTIMORE, MARYLAND 21202
                                 (410) 659-2700
 ------------------------------------------------------------------------------

                         CALCULATION OF REGISTRATION FEE

<TABLE>
<CAPTION>
==============================================================================================================================
  TITLE OF SECURITIES      AMOUNT TO BE          PROPOSED MAXIMUM                PROPOSED  MAXIMUM               AMOUNT OF
    TO BE REGISTERED      REGISTERED (1)         OFFERING PRICE PER SHARE (1)     AGGREGATE OFFERING PRICE (1)   REGISTRATION
                                                                                                                  FEE(1)
------------------------------------------------------------------------------------------------------------------------------
<S>                       <S>                    <C>                             <C>                             <C>
Common Stock, par value     500,000                    $32.563                        $16,281,500                 $4,299.00
$.01 per share, and
Series A Junior
Participation
Preferred Share
Purchase Rights
</TABLE>

------------------------------------------------------------------------------
 (1)Pursuant to Rule 457(h)(1), the proposed maximum offering price per share,
    proposed maximum aggregate offering price and the amount of the
    registration fee are based on the average of the bid and asked price of
    $32.563 per share of Guilford Pharmaceuticals Inc. common stock on February
    16, 2000 as reported on the NASDAQ National Market.


<PAGE>   2




                                     PART I

              INFORMATION REQUIRED IN THE SECTION 10(a) PROSPECTUS

    Guilford Pharmaceuticals Inc. (the "Registrant") will separately send or
give documents containing the information required to be provided in this Part I
to its employees participating in the Guilford Pharmaceuticals Inc. 1998
Employee Share Option and Restricted Share Plan, as amended August 17, 1999
(the "Plan"), as contemplated by Rule 428(b)(1) under the Securities Act of
1933, as amended (the "Securities Act"). In accordance with the instructions to
Part I of Form S-8, the Registrant will not file these documents with the
Securities and Exchange Commission (the "Commission"), either as part of this
Registration Statement or as prospectuses or prospectus supplements pursuant to
Rule 424 under the Securities Act.

                                     PART II

               INFORMATION REQUIRED IN THE REGISTRATION STATEMENT

ITEM 3.   INCORPORATION OF DOCUMENTS BY REFERENCE.

    The Registrant hereby incorporates by reference into this Registration
Statement the following documents:

    (a) Annual report on Form 10-K for the year ended December 31, 1998 filed
        with the SEC on March 30, 1999;

    (b) All reports filed with the Commission pursuant to Section 13(a) or 15
        (d) of the Securities Exchange Act of 1934, as amended (the
        "Exchange Act"), since December 31, 1998.

    (c) The description of the Registrant's common stock contained in the
        Registrant's Registration Statement on Form 8-A filed with the
        Commission on March 25, 1994, registering shares of Common Stock
        pursuant to Section 12(g) of the Exchange Act.

    In addition, all documents subsequently filed by the Registrant pursuant to
Section 13(a), 13(c), 14, or 15(d) of the Exchange Act, prior to the filing of
a post-effective amendment which indicates that all securities offered have
been sold or which deregisters all securities remaining unsold, shall be deemed
to be incorporated by reference in this Registration Statement and to be part
of hereof from the date of the filing of such documents.

    Any statement contained in a document incorporated or deemed to be
incorporated by reference shall be deemed to be modified or superseded to the
extent that a statement contained in any other subsequently filed document
which also is or is deemed to be incorporated by reference herein modifies or
supersedes such prior statement. The documents required to be so modified or
superseded shall not be deemed to constitute a part of this Registration
Statement, except as so modified or superseded.

    To the extent that any proxy statement is incorporated by reference herein,
such incorporation shall not include any information contained in such proxy
statement which is not, pursuant to the Commission's rules, deemed to be
"filed" with the Commission or subject to the liabilities of Section 18 of the
Exchange Act.

ITEM 4.   DESCRIPTION OF SECURITIES.

    A description of the Registrant's common stock, par value $ .01 per share,
is incorporated by reference under Item 3.

<PAGE>   3



ITEM 5.   INTERESTS OF NAMED EXPERTS AND COUNSEL.

         NOT APPLICABLE.

ITEM 6.   INDEMNIFICATION OF DIRECTORS AND OFFICERS.

    Under Section 145 of the Delaware General Corporation Law ("DGCL"), the
Registrant has broad powers to indemnify its directors and officers against
liabilities they may incur in such capacities, including liabilities under the
Securities Act. Article Nine of the Registrant's Amended and Restated
Certificate of Incorporation provides that the Company will indemnify its
directors and officers to the full extent permitted by law and that no director
shall be liable for monetary damages to the Registrant or its stockholders for
any breach of fiduciary duty, except to the extent provided by applicable law
(i) for any breach of the director's duty of loyalty to the Registrant or its
stockholders, (ii) for acts or omissions not in good faith or which involve
intentional misconduct or a knowing violation of law, (iii) pursuant to Section
174 of the DGCL or (iv) for any transaction from which such director derived an
improper personal benefit. In addition, under indemnification agreements with
its directors and officers, the Registrant is obligated, to the fullest extent
permissible by the DGCL, as it currently exists or may be amended, to indemnify
and hold harmless its directors and officers, from and against all expense,
liability and loss reasonably incurred or suffered by such directors and
officers.

                                    * * * * *

    Insofar as indemnification for liabilities arising under the Securities Act
may be permitted to trustees, officers, and controlling persons of the
Registrant pursuant to the foregoing provisions, or otherwise, the Registrant
has been advised that in the opinion of the Commission such indemnification is
against public policy as expressed in the Securities Act and is, therefore,
unenforceable. In the event that a claim for indemnification against such
liabilities (other than the payment by the Registrant of the expenses incurred
or paid by a trustee, officer or controlling person of the Registrant of the
successful defense of any action, suit or proceeding) is asserted by such
trustee, officer or controlling person in connection with the securities being
registered, the Registrant will, unless in the opinion of counsel the matter
has been settled by controlling precedent, submit to a court of appropriate
jurisdiction the question whether such indemnification by the Registrant is
against public policy as expressed in the Securities Act and will be governed
by the final adjudication of such issue.

ITEM 7.   EXEMPTION FROM REGISTRATION CLAIMED.

         NOT APPLICABLE.

ITEM 8.   EXHIBITS.



    EXHIBIT
    NUMBER                                 DESCRIPTION
    -------                                -----------
    4.6           Guilford Pharmaceuticals Inc. 1998 Employee Share Option and
                  Restricted Share Plan  (as amended August 17, 1999)

    5             Opinion of Hogan & Hartson L.L.P. regarding the legality of
                  the shares of Common Stock being registered (filed herewith)

   23.1           Consent of Hogan & Hartson L.L.P. (contained in Exhibit 5)

   23.2           Consent of KPMG LLP (filed herewith)

   24             Power of Attorney (contained on signature page)





<PAGE>   4

ITEM 9.   UNDERTAKINGS.

(a)   The undersigned Registrant hereby undertakes:

      (1) To file, during any period in which offers or sales are being made, a
      post-effective amendment to this Registration Statement:

            (i)  To include any prospectus required by Section 10(a)(3) of the
                 Securities Act;

           (ii)  To reflect in the prospectus any facts or events arising after
                 the effective date of the Registration Statement (or the most
                 recent post-effective amendment thereof) which, individually
                 or in the aggregate, represent a fundamental change in the
                 information set forth in the Registration Statement;

          (iii)  To include any material information with respect to the plan
                 of distribution not previously disclosed in the Registration
                 Statement or any material change to such information in the
                 Registration Statement;

      provided, however, that paragraphs (a)(1)(i) and (a)(1)(ii) do not apply
      if the information required to be included in a post-effective amendment
      by those paragraphs is contained in periodic reports filed by the
      Registrant pursuant to Section 13 or Section 15(d) of the Exchange Act
      that are incorporated by reference in this Registration Statement.

      (2) That, for the purpose of determining any liability under the
      Securities Act, each such post-effective amendment shall be deemed to be a
      new Registration Statement relating to the securities offered therein, and
      the offering of such securities at that time shall be deemed to be the
      initial bona fide offering thereof.

      (3) To remove from registration by means of a post-effective amendment any
      of the securities being registered which remain unsold at the termination
      of the offering.

  (b) The undersigned Registrant hereby undertakes that, for purposes of
      determining any liability under the Securities Act, each filing of the
      Registrant's annual report pursuant to Section 13(a) or Section 15(d) of
      the Exchange Act that is incorporated by reference in this Registration
      Statement shall be deemed to be a new Registration Statement relating to
      the securities offered therein, and the offering of such securities at
      that time shall be deemed to be the initial bona fide offering thereof.

  (c) The undertaking concerning indemnification is set forth under the
      response to Item 6.

  (d) The undersigned Registrant hereby undertakes to deliver or cause to be
      delivered with the prospectus, to each person to whom the prospectus is
      sent or given, the latest annual report, to security holders that is
      incorporated by reference in the prospectus and furnished pursuant to and
      meeting the requirements of Rule 14a-3 or 14c-3 under the Securities
      Exchange Act of 1934; and, where interim financial information required
      to be presented by Article 3 of Regulation S-X is not set forth in the
      prospectus, to deliver, or cause to be delivered to each person to whom
      the prospectus is sent or given, the latest quarterly report that is
      specifically incorporated by reference in the prospectus to provide such
      interim financial information.


<PAGE>   5


                                   SIGNATURES

Pursuant to the requirements of the Securities Act, the Registrant certifies
that it has reasonable grounds to believe that it meets all of the requirements
for filing on Form S-8 and has duly caused this Registration Statement to be
signed on its behalf by the undersigned, thereunto duly authorized, in the City
of Naples, Florida, on February 18, 2000

                          GUILFORD PHARMACEUTICALS INC.


                                   By: /s/ Craig R. Smith, M.D.
                                       ------------------------
                                       Craig R. Smith, M.D.
                                       Chief Executive Officer, President and
                                       Chairman of the Board of Directors


Pursuant to the requirements of the Securities Act of 1933, this Registration
Statement has been signed by the following persons in the capacities and on the
date indicated.

We, the undersigned officers and directors of Guilford Pharmaceuticals Inc.,
hereby severally and individually constitute and appoint Craig R. Smith, M.D.,
Andrew R. Jordan, Thomas C. Seoh, Stephen H. McElhennon and Michael J. Silver,
and each of them, the true and lawful attorneys and agents of each of us to
execute in the name, place and stead of each of us (individually and in any
capacity stated below) any and all amendments to this Registration Statement on
Form S-8, and all instruments necessary or advisable in connection therewith
and to file the same with the Securities and Exchange Commission, each of said
attorneys and agents to have power to act with or without the other and to have
full power and authority to do and perform in the name and on behalf of each of
the undersigned every act whatsoever necessary or advisable to be done in the
premises as fully and to all intents and purposes as any of the undersigned
might or could do in person, and we hereby ratify and confirm our signatures as
they may be signed by our said attorneys and agents and each of them to any and
all such amendment and amendments.


             Date:  February 18, 2000    /s/ Craig R. Smith, M.D.
                                         ------------------------
                                         Craig R. Smith, M.D.
                                         Chief Executive Officer,
                                         President and
                                         Chairman of the Board of  Directors

             Date:  February 18, 2000    /s/ Andrew R. Jordan
                                         --------------------
                                         Andrew R. Jordan
                                         Senior Vice President, Chief Financial
                                         Officer and Treasurer

             Date: February 18, 2000     /s/ George L. Bunting, Jr.
                                         ---------------------------
                                         George L. Bunting, Jr.
                                         Director

             Date:  February 18, 2000    /s/ Richard L. Casey
                                         --------------------
                                         Richard L. Casey
                                         Director

             Date:  February  18, 2000   /s/ Elizabeth M. Greetham
                                         -------------------------
                                         Elizabeth M. Greetham
                                         Director

             Date:  February  18, 2000   /s/ Joseph Klein, III
                                         ---------------------
                                         Joseph Klein, III
                                         Director

             Date:  February  18, 2000   /s/ Solomon H. Snyder, M.D.
                                         ---------------------------
                                         Solomon H. Snyder, M.D.
                                         Director

             Date: February 18, 2000     /s/ W. Leigh Thompson, M.D., Ph.D.
                                         ----------------------------------
                                         W. Leigh Thompson, M.D., Ph.D.
                                         Director




<PAGE>   6


                                  EXHIBIT INDEX



        EXHIBIT
        NUMBER                               DESCRIPTION
        ------                               -----------

          4.6      Guilford Pharmaceuticals Inc. 1998 Employee Share Option and
                   Restricted Share Plan (as amended August 17, 1999).

          5        Opinion of Hogan & Hartson L.L.P. regarding the legality of
                   the shares of Common Stock being registered

         23.1      Consent of Hogan & Hartson L.L.P. (contained in Exhibit 5)

         23.2      Consent of KPMG LLP

         24        Power of Attorney (contained on signature page)
[{"type": "S-8", "sequence": "1", "description": "FORM S-8", "secsgml_size_bytes": 18868}]
{"company-data": {"conformed-name": "GUILFORD PHARMACEUTICALS INC", "cik": "0000918066", "assigned-sic": "2834", "irs-number": "521841960", "state-of-incorporation": "DE", "fiscal-year-end": "1231"}, "filing-values": {"form-type": "S-8", "act": "33", "file-number": "333-30814", "film-number": "549900"}, "business-address": {"street1": "6611 TRIBUTARY ST", "city": "BALTIMORE", "state": "MD", "zip": "21224", "phone": "4106316300"}}
1

    As filed with the Securities and Exchange Commission on February 18, 2000
                                                    Registration No. 333-
                                                                         -----
===============================================================================

                       SECURITIES AND EXCHANGE COMMISSION
                             WASHINGTON, D.C. 20549

                          ----------------------------
                                    FORM S-8
                             REGISTRATION STATEMENT
                                      UNDER
                           THE SECURITIES ACT OF 1933

                          GUILFORD PHARMACEUTICALS INC.
             (EXACT NAME OF REGISTRANT AS SPECIFIED IN ITS CHARTER)
DELAWARE                                                                                                       52-1841960
(State or other jurisdiction of                      6611 TRIBUTARY STREET                                  (I.R.S. Employer
Incorporation or organization)                      BALTIMORE, MARYLAND 21224                             Identification  Number)
                                            (Address of principal executive offices)(Zip code)
1998 EMPLOYEE SHARE OPTION AND RESTRICTED SHARE PLAN
                            (FULL TITLE OF THE PLAN)

                              CRAIG R. SMITH, M.D.
          CHIEF EXECUTIVE OFFICER, PRESIDENT AND CHAIRMAN OF THE BOARD
                          GUILFORD PHARMACEUTICALS INC.
                              6611 TRIBUTARY STREET
                            BALTIMORE, MARYLAND 21224
                     (NAME AND ADDRESS OF AGENT FOR SERVICE)

                                 (410) 631-6300
          (TELEPHONE NUMBER, INCLUDING AREA CODE, OF AGENT FOR SERVICE)

 ------------------------------------------------------------------------------
                                 WITH A COPY TO:
                             MICHAEL J. SILVER, ESQ.
                             HOGAN & HARTSON L.L.P.
                            111 SOUTH CALVERT STREET
                            BALTIMORE, MARYLAND 21202
                                 (410) 659-2700
 ------------------------------------------------------------------------------

                         CALCULATION OF REGISTRATION FEE
==============================================================================================================================
  TITLE OF SECURITIES      AMOUNT TO BE          PROPOSED MAXIMUM                PROPOSED  MAXIMUM               AMOUNT OF
    TO BE REGISTERED      REGISTERED (1)         OFFERING PRICE PER SHARE (1)     AGGREGATE OFFERING PRICE (1)   REGISTRATION
                                                                                                                  FEE(1)
------------------------------------------------------------------------------------------------------------------------------
Common Stock, par value     500,000                    $32.563                        $16,281,500                 $4,299.00
$.01 per share, and
Series A Junior
Participation
Preferred Share
Purchase Rights
------------------------------------------------------------------------------
 (1)Pursuant to Rule 457(h)(1), the proposed maximum offering price per share,
    proposed maximum aggregate offering price and the amount of the
    registration fee are based on the average of the bid and asked price of
    $32.563 per share of Guilford Pharmaceuticals Inc. common stock on February
    16, 2000 as reported on the NASDAQ National Market.
2

                                     PART I

              INFORMATION REQUIRED IN THE SECTION 10(a) PROSPECTUS

    Guilford Pharmaceuticals Inc. (the "Registrant") will separately send or
give documents containing the information required to be provided in this Part I
to its employees participating in the Guilford Pharmaceuticals Inc. 1998
Employee Share Option and Restricted Share Plan, as amended August 17, 1999
(the "Plan"), as contemplated by Rule 428(b)(1) under the Securities Act of
1933, as amended (the "Securities Act"). In accordance with the instructions to
Part I of Form S-8, the Registrant will not file these documents with the
Securities and Exchange Commission (the "Commission"), either as part of this
Registration Statement or as prospectuses or prospectus supplements pursuant to
Rule 424 under the Securities Act.

                                     PART II

               INFORMATION REQUIRED IN THE REGISTRATION STATEMENT

ITEM 3.   INCORPORATION OF DOCUMENTS BY REFERENCE.

    The Registrant hereby incorporates by reference into this Registration
Statement the following documents:

    (a) Annual report on Form 10-K for the year ended December 31, 1998 filed
        with the SEC on March 30, 1999;

    (b) All reports filed with the Commission pursuant to Section 13(a) or 15
        (d) of the Securities Exchange Act of 1934, as amended (the
        "Exchange Act"), since December 31, 1998.

    (c) The description of the Registrant's common stock contained in the
        Registrant's Registration Statement on Form 8-A filed with the
        Commission on March 25, 1994, registering shares of Common Stock
        pursuant to Section 12(g) of the Exchange Act.

    In addition, all documents subsequently filed by the Registrant pursuant to
Section 13(a), 13(c), 14, or 15(d) of the Exchange Act, prior to the filing of
a post-effective amendment which indicates that all securities offered have
been sold or which deregisters all securities remaining unsold, shall be deemed
to be incorporated by reference in this Registration Statement and to be part
of hereof from the date of the filing of such documents.

    Any statement contained in a document incorporated or deemed to be
incorporated by reference shall be deemed to be modified or superseded to the
extent that a statement contained in any other subsequently filed document
which also is or is deemed to be incorporated by reference herein modifies or
supersedes such prior statement. The documents required to be so modified or
superseded shall not be deemed to constitute a part of this Registration
Statement, except as so modified or superseded.

    To the extent that any proxy statement is incorporated by reference herein,
such incorporation shall not include any information contained in such proxy
statement which is not, pursuant to the Commission's rules, deemed to be
"filed" with the Commission or subject to the liabilities of Section 18 of the
Exchange Act.

ITEM 4.   DESCRIPTION OF SECURITIES.

    A description of the Registrant's common stock, par value $ .01 per share,
is incorporated by reference under Item 3.
3

ITEM 5.   INTERESTS OF NAMED EXPERTS AND COUNSEL.

         NOT APPLICABLE.

ITEM 6.   INDEMNIFICATION OF DIRECTORS AND OFFICERS.

    Under Section 145 of the Delaware General Corporation Law ("DGCL"), the
Registrant has broad powers to indemnify its directors and officers against
liabilities they may incur in such capacities, including liabilities under the
Securities Act. Article Nine of the Registrant's Amended and Restated
Certificate of Incorporation provides that the Company will indemnify its
directors and officers to the full extent permitted by law and that no director
shall be liable for monetary damages to the Registrant or its stockholders for
any breach of fiduciary duty, except to the extent provided by applicable law
(i) for any breach of the director's duty of loyalty to the Registrant or its
stockholders, (ii) for acts or omissions not in good faith or which involve
intentional misconduct or a knowing violation of law, (iii) pursuant to Section
174 of the DGCL or (iv) for any transaction from which such director derived an
improper personal benefit. In addition, under indemnification agreements with
its directors and officers, the Registrant is obligated, to the fullest extent
permissible by the DGCL, as it currently exists or may be amended, to indemnify
and hold harmless its directors and officers, from and against all expense,
liability and loss reasonably incurred or suffered by such directors and
officers.

                                    * * * * *

    Insofar as indemnification for liabilities arising under the Securities Act
may be permitted to trustees, officers, and controlling persons of the
Registrant pursuant to the foregoing provisions, or otherwise, the Registrant
has been advised that in the opinion of the Commission such indemnification is
against public policy as expressed in the Securities Act and is, therefore,
unenforceable. In the event that a claim for indemnification against such
liabilities (other than the payment by the Registrant of the expenses incurred
or paid by a trustee, officer or controlling person of the Registrant of the
successful defense of any action, suit or proceeding) is asserted by such
trustee, officer or controlling person in connection with the securities being
registered, the Registrant will, unless in the opinion of counsel the matter
has been settled by controlling precedent, submit to a court of appropriate
jurisdiction the question whether such indemnification by the Registrant is
against public policy as expressed in the Securities Act and will be governed
by the final adjudication of such issue.

ITEM 7.   EXEMPTION FROM REGISTRATION CLAIMED.

         NOT APPLICABLE.

ITEM 8.   EXHIBITS.

    EXHIBIT
    NUMBER                                 DESCRIPTION
    -------                                -----------
    4.6           Guilford Pharmaceuticals Inc. 1998 Employee Share Option and
                  Restricted Share Plan  (as amended August 17, 1999)

    5             Opinion of Hogan & Hartson L.L.P. regarding the legality of
                  the shares of Common Stock being registered (filed herewith)

   23.1           Consent of Hogan & Hartson L.L.P. (contained in Exhibit 5)

   23.2           Consent of KPMG LLP (filed herewith)

   24             Power of Attorney (contained on signature page)
4

ITEM 9.   UNDERTAKINGS.

(a)   The undersigned Registrant hereby undertakes:

      (1) To file, during any period in which offers or sales are being made, a
      post-effective amendment to this Registration Statement:

            (i)  To include any prospectus required by Section 10(a)(3) of the
                 Securities Act;

           (ii)  To reflect in the prospectus any facts or events arising after
                 the effective date of the Registration Statement (or the most
                 recent post-effective amendment thereof) which, individually
                 or in the aggregate, represent a fundamental change in the
                 information set forth in the Registration Statement;

          (iii)  To include any material information with respect to the plan
                 of distribution not previously disclosed in the Registration
                 Statement or any material change to such information in the
                 Registration Statement;

      provided, however, that paragraphs (a)(1)(i) and (a)(1)(ii) do not apply
      if the information required to be included in a post-effective amendment
      by those paragraphs is contained in periodic reports filed by the
      Registrant pursuant to Section 13 or Section 15(d) of the Exchange Act
      that are incorporated by reference in this Registration Statement.

      (2) That, for the purpose of determining any liability under the
      Securities Act, each such post-effective amendment shall be deemed to be a
      new Registration Statement relating to the securities offered therein, and
      the offering of such securities at that time shall be deemed to be the
      initial bona fide offering thereof.

      (3) To remove from registration by means of a post-effective amendment any
      of the securities being registered which remain unsold at the termination
      of the offering.

  (b) The undersigned Registrant hereby undertakes that, for purposes of
      determining any liability under the Securities Act, each filing of the
      Registrant's annual report pursuant to Section 13(a) or Section 15(d) of
      the Exchange Act that is incorporated by reference in this Registration
      Statement shall be deemed to be a new Registration Statement relating to
      the securities offered therein, and the offering of such securities at
      that time shall be deemed to be the initial bona fide offering thereof.

  (c) The undertaking concerning indemnification is set forth under the
      response to Item 6.

  (d) The undersigned Registrant hereby undertakes to deliver or cause to be
      delivered with the prospectus, to each person to whom the prospectus is
      sent or given, the latest annual report, to security holders that is
      incorporated by reference in the prospectus and furnished pursuant to and
      meeting the requirements of Rule 14a-3 or 14c-3 under the Securities
      Exchange Act of 1934; and, where interim financial information required
      to be presented by Article 3 of Regulation S-X is not set forth in the
      prospectus, to deliver, or cause to be delivered to each person to whom
      the prospectus is sent or given, the latest quarterly report that is
      specifically incorporated by reference in the prospectus to provide such
      interim financial information.
5

                                   SIGNATURES

Pursuant to the requirements of the Securities Act, the Registrant certifies
that it has reasonable grounds to believe that it meets all of the requirements
for filing on Form S-8 and has duly caused this Registration Statement to be
signed on its behalf by the undersigned, thereunto duly authorized, in the City
of Naples, Florida, on February 18, 2000

                          GUILFORD PHARMACEUTICALS INC.

                                   By: /s/ Craig R. Smith, M.D.
                                       ------------------------
                                       Craig R. Smith, M.D.
                                       Chief Executive Officer, President and
                                       Chairman of the Board of Directors

Pursuant to the requirements of the Securities Act of 1933, this Registration
Statement has been signed by the following persons in the capacities and on the
date indicated.

We, the undersigned officers and directors of Guilford Pharmaceuticals Inc.,
hereby severally and individually constitute and appoint Craig R. Smith, M.D.,
Andrew R. Jordan, Thomas C. Seoh, Stephen H. McElhennon and Michael J. Silver,
and each of them, the true and lawful attorneys and agents of each of us to
execute in the name, place and stead of each of us (individually and in any
capacity stated below) any and all amendments to this Registration Statement on
Form S-8, and all instruments necessary or advisable in connection therewith
and to file the same with the Securities and Exchange Commission, each of said
attorneys and agents to have power to act with or without the other and to have
full power and authority to do and perform in the name and on behalf of each of
the undersigned every act whatsoever necessary or advisable to be done in the
premises as fully and to all intents and purposes as any of the undersigned
might or could do in person, and we hereby ratify and confirm our signatures as
they may be signed by our said attorneys and agents and each of them to any and
all such amendment and amendments.

             Date:  February 18, 2000    /s/ Craig R. Smith, M.D.
                                         ------------------------
                                         Craig R. Smith, M.D.
                                         Chief Executive Officer,
                                         President and
                                         Chairman of the Board of  Directors

             Date:  February 18, 2000    /s/ Andrew R. Jordan
                                         --------------------
                                         Andrew R. Jordan
                                         Senior Vice President, Chief Financial
                                         Officer and Treasurer

             Date: February 18, 2000     /s/ George L. Bunting, Jr.
                                         ---------------------------
                                         George L. Bunting, Jr.
                                         Director

             Date:  February 18, 2000    /s/ Richard L. Casey
                                         --------------------
                                         Richard L. Casey
                                         Director

             Date:  February  18, 2000   /s/ Elizabeth M. Greetham
                                         -------------------------
                                         Elizabeth M. Greetham
                                         Director

             Date:  February  18, 2000   /s/ Joseph Klein, III
                                         ---------------------
                                         Joseph Klein, III
                                         Director

             Date:  February  18, 2000   /s/ Solomon H. Snyder, M.D.
                                         ---------------------------
                                         Solomon H. Snyder, M.D.
                                         Director

             Date: February 18, 2000     /s/ W. Leigh Thompson, M.D., Ph.D.
                                         ----------------------------------
                                         W. Leigh Thompson, M.D., Ph.D.
                                         Director
6

                                  EXHIBIT INDEX

        EXHIBIT
        NUMBER                               DESCRIPTION
        ------                               -----------

          4.6      Guilford Pharmaceuticals Inc. 1998 Employee Share Option and
                   Restricted Share Plan (as amended August 17, 1999).

          5        Opinion of Hogan & Hartson L.L.P. regarding the legality of
                   the shares of Common Stock being registered

         23.1      Consent of Hogan & Hartson L.L.P. (contained in Exhibit 5)

         23.2      Consent of KPMG LLP

         24        Power of Attorney (contained on signature page)