OBJECTIVES: To compare the rates of infection and wound complications in patients undergoing operative fixation (ORIF) of acetabular fractures receiving heterotopic ossification (HO) prophylaxis using indomethacin or external beam radiation therapy (XRT) versus no prophylaxis. DESIGN: Retrospective cohort. SETTING: Level I trauma center. PATIENTS: We reviewed 473 patients undergoing ORIF of acetabular fractures through posterior, combined, or extensile surgical approaches from 2012 to 2017, with a median follow-up of 13 months (0.5-77 months). MAIN OUTCOME MEASUREMENT: Rates of infection and wound complications were stratified according to their HO prophylaxis method into three groups as indomethacin, XRT, and no prophylaxis. RESULTS: Overall, 167 patients (35.3%) received indomethacin, 104 patients (22.0%) received postoperative XRT, and 202 patients (42.7%) received no prophylactic treatment. There was no difference between the 3 groups for the risk of surgical site infection (P = 0.280). The XRT group had a significantly increased risk of noninfectious wound complications (20.2%) compared with the indomethacin group (6.6%, P = 0.002) and the no prophylaxis group (5.0%, P < 0.0001). Multivariate analysis revealed XRT remained a significant risk factor for noninfectious wound complications compared with no prophylaxis (odds ratio 5.39; 95% confidence interval 2.37-12.22; P < 0.0001). CONCLUSIONS: Although there is no difference between XRT, indomethacin, and no HO prophylaxis for the risk of surgical site infection, the use of XRT results in more than 5 times increased risk of noninfectious wound complications compared with no prophylaxis. This increased risk should be considered when contemplating XRT for HO prophylaxis in acetabular fracture patients. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.