United States securities and exchange commission logo March 17, 2021 Ankit Mahadevia, M.D. President and Chief Executive Officer Spero Therapeutics, Inc. 675 Massachusetts Avenue, 14th Floor Cambridge, Massachusetts 02139 Re: Spero Therapeutics, Inc. Registration Statement on Form S-3 Filed March 11, 2021 File No. 333-254170 Dear Dr. Mahadevia: This is to advise you that we have not reviewed and will not review your registration statement. Please refer to Rules 460 and 461 regarding requests for acceleration. We remind you that the company and its management are responsible for the accuracy and adequacy of their disclosures, notwithstanding any review, comments, action or absence of action by the staff. Please contact Alan Campbell at 202-551-4224 with any questions. Sincerely, Division of Corporation Finance Office of Life Sciences cc: Matthew J. Gardella, Esq.