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Infectious, wound and soft tissue events contribute to the morbidity of radical cystectomy but the association between these events and antibiotic prophylaxis is not clear. We sought to describe the contemporary use of antibiotic prophylaxis in radical cystectomy and adherence to published guidelines, and identify regimens with the lowest rates of infectious events.We identified the intraoperative antibiotic prophylaxis regimen in a population based, retrospective cohort study of patients who underwent radical cystectomy across the United States between 2003 and 2013. Multivariable regression was done to evaluate 90-day infectious events and length of stay.In a weighted cohort of 52,349 patients there were 579 unique antibiotic prophylaxis regimens. Cefazolin was the most commonly used antibiotic (16% of cases). The overall infectious event rate was 25%. Only 15% of patients received antibiotic prophylaxis based on guidelines. Of guideline based antibiotic prophylaxis ampicillin/sulbactam had the lowest odds of infectious events (OR 0.34, p <0.001). In 2.7% of patients a penicillin based regimen with a β-lactamase inhibitor was associated with a prominent reduction in the odds of infectious events (OR 0.45, p = 0.001) and decreased length of stay (–1.3 days, p = 0.016).Antibiotic prophylaxis practices are highly heterogeneous in radical cystectomy. There is a lack of adherence to published guidelines. We observed decreased infectious event rates and shorter length of stay with regimens that included broad coverage of common skin, genitourinary and gastrointestinal flora. The ideal antibiotic regimen requires further study to optimize perioperative outcomes.