Background: Providers exhibit variation in the selection of the class, dose, and duration of prescribed antibiotic prophylaxis (ABP) to prevent postsurgical infections. We sought to evaluate ABP practice patterns for common inpatient urologic oncology surgeries and ascertain the association between extended ABP and hospital-acquired Clostridium difficile (C. diff) infections. Methods: From the PREMIER database for 2007–2012, we identified patients who underwent radical prostatectomy (RP), radical or partial nephrectomy (Nephx), or radical cystectomy (RC). We defined extended ABP from charges for antibiotics ≥ 2 days after surgery; exclusive of patients with a switch in antibiotic class within 2 postoperative days for presumption of infection. We identified postoperative C. diff infections using ICD-9 diagnosis codes. Hierarchical linear regression models were constructed by procedure to identify patient and provider factors associated with extended ABP. Logistic regression models evaluated the association between extended ABP and postoperative C. diff infection, adjusting for patient and provider characteristics. Results: We identified 59,184 RP patients, 27,921 Nephx patients, and 5,425 RC patients. RC patients were more likely to receive extended ABP (56%) than RP (18%) or Nephx (29%) patients (p<0.001). Other factors associated with extended ABP included prolonged postoperative length of stay (OR ≥ 1.69, p<0.001 for all procedures), and surgical volume (p<0.001 for highest vs. lowest volume quartiles). Hospital identity explained 35% of the variability in ABP after RP, 23% after Nephx, and 20% after RC. Among Nephx and RC patients, extended ABP was associated with significantly higher odds of postoperative C. diff infection (OR 3.79, 95% CI 2.46–5.84, and OR 1.64, 95% CI 1.12–2.39, respectively). Conclusions: We identified marked hospital-level variability in extended ABP following RP, Nephx, and RC, which was associated with significantly increased odds of hospital-acquired C. diff infections. Efforts to increase provider compliance with national ABP guidelines may decrease preventable hospital-acquired infections after urologic cancer surgery.