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Background: The administration of antibiotic prophylaxis for clean-wound surgeries is controversial among surgeons, despite guidelines suggesting its use. This study aimed to evaluate its effectiveness in preventing surgical site infections (SSIs) in clean-wound surgeries within a regional setting with varied practices regarding prophylaxis. Materials and methods: This retrospective cohort study included four types of common general surgeries performed from March 2021 to February 2023 at a tertiary regional hospital in Thailand. The surgeries included skin/subcutaneous excision, thyroidectomy, inguinal hernia repair, and breast surgeries, all of which required regional or general anesthesia. Antibiotic prophylaxis was administered at the discretion of the attending surgeons. SSI diagnosis followed standard diagnostic criteria, involving reviewing medical records and the records of the infection control unit. Infection risk factors were examined. The primary outcome comparison used inverse probability treatment weighting of propensity scores, with covariate balance evaluated. Results: Of the 501 surgeries identified, 84 were excluded, leaving 417 eligible for analysis. Among these patients, 233 received prophylactic antibiotics, for an SSI rate of 1.3%, while 184 did not receive antibiotics, for an SSI rate of 2.2%. A comparative analysis using propensity score weighting revealed no statistically significant difference in the incidence of SSI between the groups (risk ratio [95% confidence interval]: 0.54 (0.11, 2.50), p = 0.427). Conclusion: In this practical setting, with the given study size, antibiotic prophylaxis in common general surgeries involving clean wounds did not significantly prevent SSIs. Routine use recommendations should be re-evaluated. Trial registration: Not applicable as this study is a retrospective cohort study and not a clinical trial. [ABSTRACT FROM AUTHOR]