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Background: The impact of antibiotics (ATBs) on the risk of colorectal cancer (CRC) recurrence after curative resection remains unknown., Methods: Using the French nation-wide database of cancer patients, all newly diagnosed non-metastatic CRC patients resected between 01/2012 and 12/2014 were included. The perioperative ATB intake (from 6 months before surgery until 1 year after) was classified according to the class, the period of use (pre- vs post-resection), the disease stage (localized and locally advanced), and the primary tumor location (colon and rectum/junction). The primary endpoint was the 3-year disease-free survival (DFS). The impact of ATB was assessed using time-dependent multivariate Cox models., Results: A total of 35,496 CRC patients were included. Seventy-nine percent of patients had at least one ATB intake. Outpatient ATB intake after surgery was associated with unfavorable 3-year DFS. The ATBs associated with decreased 3-year DFS were cephalosporins, streptogramins, quinolones, penicillin A with beta-lactamase inhibitors, and antifungals with differential effects according to the primary tumor location and disease stage., Conclusion: These findings suggest that ATBs modulate the risk of recurrence after early CRC resection with a differential impact of the ATB classes depending on disease stage and tumor site., Competing Interests: Conflicts of interest A.T. reports personal fees from SERVIER, personal fees from MYLAN, personal fees from MERCK SERONO, personal fees from AMGEN, non-financial support from MERCK, non-financial support from SANOFI, non-financial support from PFIZER, outside the submitted work. C.B. reports personal fees and non-financial support from Da Volterra, personal fees from MYLAN, outside the submitted work. J.V. reports personal fees from BMS, personal fees from Merck-Serono, personal fees from Novartis, personal fees from Guardant Health, personal fees from Sanofi, outside the submitted work. A.A. reports personal fees and other from DaVolterra, outside the submitted work; In addition, A.A. has a patent DaVolterra issued. B.R. reports consulting/advisory role for Neophore, Bayer, Roche, Novartis, Gilead, Servier; Travel, accommodations, and expenses from Bayer, Servier, Astellas; salary support from Nuovo Soldati Foundation in 2019 and funding including salary support from Swim Across America foundation in 2020. The remaining authors disclose no conflicts., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)