OBJECTIVES: To compare the risks of surgical site infection (SSI) and postoperative complications after acetabular fracture open reduction internal fixation (ORIF) in patients receiving topical intrawound antibiotic powder compared with those not receiving antibiotic powder (control group). DESIGN: Retrospective cohort. SETTING: Level I trauma center. PATIENTS AND INTERVENTION: We reviewed 789 acetabular fracture ORIF cases from 2010 to 2019 at our institution, with mean follow-up of 18 months (3-112 months). Overall, 326 patients comprised the control group and 463 received topical antibiotic powder (294 vancomycin and 169 vancomycin/tobramycin). MAIN OUTCOME MEASUREMENT: The study groups were compared for risk of SSI, seroma formation, wound dehiscence, acute kidney injury (AKI), and other postoperative complications. RESULTS: There were 63 total SSI (8.0%), 50 (6.3%) deep SSI and 13 suprafascial SSI (1.6%) cases. There was no difference in the risk of total SSI (8.3% vs. 7.8%, P = 0.80) or deep SSI (6.1% vs. 6.5%, P = 0.64). This was confirmed by multivariate analysis adjusting for covariates (odds ratio = 0.93; 95% confidence interval, 0.52-1.67; P = 0.80). Similar results were demonstrated when comparing the control group with the vancomycin and vancomycin/tobramycin subgroups. The control group and antibiotic powder groups had similar risks of all outcomes of interest, including seroma formation (1.8% vs. 1.7%, P = 1.00), wound dehiscence (1.2% vs. 2.2%, P = 0.42), total AKI (5.2% vs. 8.2%, P = 0.12), and RIFLE classification AKI (injury; 0.9% vs. 2.2%, P = 0.50). CONCLUSIONS: The addition of topical intrawound antibiotic powder, whether vancomycin alone or vancomycin/tobramycin before closure, does not reduce the risk of SSI after acetabular fracture ORIF compared with standard normal saline irrigation alone. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.