OBJECTIVE We aimed to measure the association between 2013 guideline concordant prophylactic antibiotic use prior to surgery and infection with Clostridium difficile. METHODS We conducted a retrospective case-control study by selecting patients who underwent a surgical procedure between January 1, 2012 and December 31, 2013. METHODS Large urban community hospital. METHODS Cases and controls were patients age 18+ years who underwent an eligible surgery (i.e., colorectal, neurosurgery, vascular/cardiac/thoracic, hysterectomy, abdominal/pelvic and orthopedic surgical procedures) within six months prior to infection diagnosis. Cases were diagnosed with C. difficile infection while controls were not. METHODS The primary exposure was receiving (vs. not receiving) the recommended prophylactic antibiotic regimen, based on type and duration. Potential confounders included age, sex, length of hospital stay, comorbidities, type of surgery, and prior antibiotic use. Crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression. RESULTS We enrolled 68 cases and 220 controls. The adjusted OR among surgical patients between developing C. difficile infection and not receiving the recommended prophylactic antibiotic regimen (usually receiving antimicrobial prophylaxis for more than 24 hours) was 6.7 (95% CI: 2.9-15.5). Independent risk factors for developing C. difficile infection included having severe comorbidities, receiving antibiotics within the previous 6 months, and undergoing orthopedic surgery. CONCLUSIONS Adherence to the recommended prophylactic antibiotics among surgical patients likely reduces the probability of being case of C. difficile. Antibiotic stewardship should be a priority in strategies to decrease the morbidity, mortality, and costs associated with C. difficile infection.