Background: Prostate biopsy is a common procedure that many U.S. men endure during their lifetime. Evidence suggests that the risk of post-biopsy infections is increasing. We aimed to characterize risk factors for post-biopsy infections using nationally representative data. Methods: We analyzed Surveillance, Epidemiology and End Results (SEER)-Medicare data to identify 246,299 male Medicare beneficiaries aged over 65 years who underwent prostate biopsy between 2001 and 2013. Multivariable logistic regression was used to assess risk factors for post-biopsy infection.The primary outcomes were any infection within 30 days of prostate biopsy, and infections requiring hospital admission within 30 days of biopsy. Results: In this cohort, 7.0% of men developed an infection within 30 days and 1.0% required hospital admission for infection. The vast majority of biopsies were performed transrectally (99.5%) without a rectal swab culture performed prior to biopsy to direct antimicrobial prophylaxis (99.7%). Risk factors for post-biopsy infection and hospitalization on multivariable analysis included age over 80 years, odds ratio (OR) 1.23 (95% confidence interval (CI) 1.17 to 1.29, for any infection, and OR 1.71 (95% CI 1.52 to 1.92) for infection requiring hospitalization, Black race, OR 1.29 (95% CI 1.23 to 1.35) for any infection, and OR 1.41 (95% CI 1.25 to 1.58) for hospitalization, and Hispanic ethnicity, OR 1.61 (95% CI 1.46 to 1.77) for any infection, and OR 1.92 (95% CI 1.52 to 2.42) for hospitalization. The risk of infection also increased with Charlson score of 3 or greater, OR 1.32 (95% CI 1.25 to 1.39), and OR 2.04 (95% CI 1.73 to 2.40) for any infection or hospitalization, respectively. High surgeon volume (>11.6 cases) was protective, OR 0.92 (95% CI 0.88 to 0.96) for any infection, and OR 0.76 (95% CI 0.69 to 0.85) for hospitalization. Conclusions: Among other factors, we identify patient age, Charlson score, race, ethnicity, and surgeon volume as significant predictors of post-prostate biopsy infection and hospitalization. These results should aid in identifying patients who may benefit from alternative techniques, such as targeted or augmented antimicrobial prophylaxis, or transperineal biopsy, to minimize this common source of morbidity.