Background: Determining predictors of surgical site infection (SSI) in a large cohort is important for the design of accurate SSI surveillance programs. We hypothesized that additional organ resection and pelvic exenterative procedures are associated independently with a higher risk of SSI. Methods: Patients in the American College of Surgeons National Surgical Quality Improvement Program® (ACS NSQIP®; American College of Surgeons, Chicago, IL) database (2005-2012) were identified (n=112,282). Surgical site infection (superficial or deep SSI) at 30 d was the primary outcome. Using primary and secondary CPT® codes (American Medical Association, Chicago, IL) pelvic exenteration was defined and additional organ resection was defined as: bladder resection/repair, hysterectomy, partial vaginectomy, additional segmental colectomy, small bowel, gastric, or diaphragm resection. Univariable analysis of patient and procedure factors identified significant (p<0.05) predictors, which were modeled using stepwise logistic regression. Results: The rate of SSI was 9.2%. After adjusting for operative duration, predictors of SSI were body mass index (BMI) 25-29.9 (odds ratio [OR]: 1.3), BMI 30-34.9 (OR: 1.59), BMI 35-39.9 (OR: 2.11), BMI>40 (OR: 2.51), pulmonary comorbidities (OR: 1.22), smoking (OR: 1.24), bowel obstruction (OR: 1.40), wound classification 3 or 4 (OR: 1.18), and abdominoperineal resection (OR: 1.58). Laparoscopic or laparoscopically assisted procedures offered a protective effect against incision infection (OR: 0.55). Additional organ resection (OR: 1.08) was also associated independently with SSI, but the magnitude of the effect was decreased after accounting for operative duration. In the analysis that excludes operative duration, pelvic exenteration is associated with SSI (OR: 1.38), but incorporating operative duration into the model results in this variable becoming non-significant. Conclusions: In addition to other factors, obesity, surgery for bowel obstruction, abdominoperineal resection, and additional organ resection are independently associated with a higher risk of SSI. Surgical site infection risk in pelvic exenteration and multiple organ resection cases appears to be mediated by prolonged operative duration. In these established high-risk sub-groups of patients, aggressive interventions to prevent SSI should be implemented.