Initial Registration Statement for Employee Benefit Plan (Form S-8)

As filed with the Securities and Exchange Commission on March 10, 2026

Registration No. 333-

UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

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FORM S-8

REGISTRATION STATEMENT

UNDER THE

SECURITIES ACT OF 1933

________________

PRELUDE THERAPEUTICS INCORPORATED

(Exact name of registrant as specified in its charter)

Indicate by check mark whether the Registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or an emerging growth company. See the definition of "large accelerated filer", "accelerated filer", "smaller reporting company", and "emerging growth company" in Rule 12b-2 of the Exchange Act.

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 7(a)(2)(B) of the Securities Act. ☐

REGISTRATION OF ADDITIONAL SHARES

PURSUANT TO GENERAL INSTRUCTION E

Prelude Therapeutics Incorporated (the "Registrant") is filing this Registration Statement with the Securities and Exchange Commission (the "Commission") to register the offer and sale of (a) 3,147,681 additional shares of the Registrant's common stock, par value $0.0001 per share (the "Common Stock") available for issuance under the Registrant's 2020 Equity Incentive Plan ("2020 EIP"), pursuant to the provision of the 2020 EIP providing for an annual 5% automatic increase in the number of shares reserved for issuance and (b) 629,536 additional shares of Common Stock available for issuance under the Registrant's 2020 Employee Stock Purchase Plan ("2020 ESPP"), pursuant to the provision of the 2020 ESPP providing for an annual 1% automatic increase in the number of shares reserved for issuance.

In accordance with General Instruction E of Form S-8, and only with respect to the Common Stock issuable under the 2020 EIP and 2020 ESPP, this Registration Statement hereby incorporates by reference the contents of the Registrant's Registration Statement on Form S-8 filed with the Commission on September 25, 2020 (Registration No. 333-249032), March 16, 2021 (Registration No. 333-254349), March 17, 2022 (Registration No. 333-263642), March 15, 2023 (File No. 333-270549), February 16, 2024 (File No. 333-277122), and March 10, 2025 (File No. 333-285662) to the extent not superseded hereby.

PART II

INFORMATION REQUIRED IN THE REGISTRATION STATEMENT

Item 3. Incorporation of Documents by Reference.

The following documents filed by the Registrant with the Commission pursuant to the Securities Exchange Act of 1934, as amended (the "Exchange Act") are incorporated herein by reference:

(a) the Registrant's Annual Report on Form 10-K for the year ended December 31, 2025, filed with the Commission on March 10, 2026;

(b) our Current Reports on Form 8-K, filed with the Commission on January 9, 2026 and February 3, 2026; and

(c) the description of the Common Stock contained in the Registrant's registration statement on Form 8-A (File No. 001-39527) filed on September 16, 2020 under Section 12(b) of the Exchange Act, including any amendment or report filed for the purpose of updating such description, including Exhibit 4.5 of the Registrant's Annual Report on Form 10-K for the year ended December 31, 2023, filed with the Commission on February 15, 2024 (File No. 001-39527).

All documents subsequently filed by the Registrant pursuant to Section 13(a), 13(c), 14 or 15(d) of the Exchange Act subsequent to the filing of this Registration Statement and prior to the filing of a post-effective amendment which indicates that all securities offered hereby have been sold or which deregisters all securities then remaining unsold, shall be deemed to be incorporated by reference into this Registration Statement and to be a part hereof from the date of filing such documents, except that information furnished to the Commission under Item 2.02 or Item 7.01 in Current Reports on Form 8-K and any exhibit relating to such information, shall not be deemed to be incorporated by reference in this Registration Statement. Any statement contained in a document incorporated or deemed to be incorporated by reference herein shall be deemed to be modified or superseded for purposes of this Registration Statement to the extent that a statement contained in any subsequently filed document which also is deemed to be incorporated by reference herein modifies or supersedes such statement.

Item 8. Exhibits.

The following exhibits are filed herewith:

SIGNATURES

Pursuant to the requirements of the Securities Act of 1933, 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 Wilmington, State of Delaware, on this 10th day of March, 2026.

PRELUDE THERAPEUTICS INCORPORATED

POWER OF ATTORNEY

KNOW ALL PERSONS BY THESE PRESENTS, that each person whose signature appears below hereby constitutes and appoints Krishna Vaddi and Bryant Lim, and each of them, as his or her true and lawful attorney-in-fact and agent with full power of substitution, for him or her in any and all capacities, to sign any and all amendments (including post-effective amendments) to this Registration Statement on Form S-8, and to file the same, with all exhibits thereto and other documents in connection therewith, with the Securities and Exchange Commission, granting unto said attorney-in-fact and agent full power and authority to do and perform each and every act and thing requisite and necessary to be done in connection therewith, as fully for all intents and purposes as he might or could do in person, hereby ratifying and confirming all that said attorney-in-fact and agent, or his or her substitute, may lawfully do or cause to be done by virtue hereof.

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