OBJECTIVE Clostridium difficile infection (CDI) is a common hospital-acquired infection. Previous reports on the incidence, risk factors, and impact of CDI on resources in the surgical population are limited. In this context, we study CDI across diverse surgical settings. METHODS We prospectively identified patients with laboratory-confirmed postoperative CDI after 40 different general, vascular, or gynecologic surgeries at 52 academic and community hospitals between July 2012 and September 2013. We used multivariable regression models to identify CDI risk factors and to determine the impact of CDI on resource utilization. RESULTS Of 35,363 patients, 179 (0.51%) developed postoperative CDI. The highest rates of CDI occurred after lower-extremity amputation (2.6%), followed by bowel resection or repair (0.9%) and gastric or esophageal operations (0.7%). Gynecologic and endocrine operations had the lowest rates (0.1% and 0%, respectively). By multivariable analyses, older age, chronic immunosuppression, hypoalbuminemia (≤3.5 g/dL), and preoperative sepsis were associated with CDI. Use of prophylactic antibiotics was not independently associated with CDI, neither was sex, body mass index (BMI), surgical priority, weight loss, or comorbid conditions. Three procedure groups had higher odds of postoperative CDI: lower-extremity amputations (adjusted odds ratio [aOR], 3.5; P=.03), gastric or esophageal operations (aOR, 2.1; P=.04), and bowel resection or repair (aOR, 2; P=.04). Postoperative CDI was independently associated with increased length of stay (mean, 13.7 d vs 4.5 d), emergency department presentations (18.9 vs 9.1%) and readmissions (38.9% vs 7.2%, all P<.001). CONCLUSIONS Incidence of postoperative CDI varies by surgical procedure. Postoperative CDI is also associated with higher rates of extended length of stay, emergency room presentations, and readmissions, which places a potentially preventable burden on hospital resources.