Preoperative antibiotic prophylaxis and surgical technological advances have greatly reduced, but not totally eliminated surgical site infection (SSI) posthysterectomy. We aimed to identify risk factors for SSI posthysterectomy among women with a high prevalence of gynecologic malignancies, in a tertiary care setting where compliance with the Joint Commission's Surgical Care Improvement Project core measures is excellent. The study was a matched case-control, 2 controls per case, matched on date of surgery. Study time was January 2, 2012-December 31, 2015. Procedures included abdominal and vaginal hysterectomies (open, laparoscopic, and robotic). SSI (superficial incisional or deep/organ/space) was defined as within 30 days postoperatively, per Centers for Disease Control and Prevention criteria. Statistical analysis included bivariate analysis and conditional logistic regression controlling for demographic and clinical variables, both patient-related and surgery-related, including detailed prophylactic antibiotic exposure. Of the total 1,531 hysterectomies performed, we identified 52 SSIs (3%), with 60% being deep incisional or organ/space infections. All case patients received appropriate preoperative antibiotics (timing, choice, and weight-based dosing). Bivariate analysis showed that higher median weight, higher median Charlson comorbidity index, immune suppressed state, American Society of Anesthesiologists score ≥ 3, prior surgery within 60 days, clindamycin/gentamicin prophylaxis, surgery involving the omentum or gastrointestinal tract, longer surgery duration, ≥4 surgeons present in the operating room, higher median blood loss, ≥7 catheters or invasive devices in the operating room, and higher median length of hospital stay increased SSI risk (P < .05 for all). Cefazolin preoperative prophylaxis, robot-assisted surgery, and laparoscopic surgery were protective (P < .05 for all). Duration of surgery was the only independent risk factor for SSI identified on multivariate analysis (odds ratio, 3.45; 95% confidence interval, 1.21-9.76; P = .02). In our population of women with multimorbidity and hysterectomies largely due to underlying gynecologic malignancies, duration of surgery, presumed a marker of surgical complexity, is a significant SSI risk factor. The choice of preoperative antibiotic did not alter SSI risk in our study.