Introduction: Some authors advocate an increase in post-prostate needle biopsy (PNB) infections associated with emergent quinolone resistance in E. coli, urging re-evaluation of antibioprophylaxis. In this study, we compared rates of post-PNB urosepsis associated with two oral regimens of antibioprophylaxis: ciprofloxacin (CIP) vs. ciprofloxacin and fosfomycin tromethamine combination (CIP/FOS). Methods: This retrospective pre-post intervention study included all patients who underwent PNB in two Canadian hospitals from January 2012 to December 2015. The primary outcome was urosepsis within one month of PNB. Urosepsis rates were analyzed according to antibioprophylaxis using log-binomial regression, considering the propensity scores weights of collected risk factor data. Results: We reviewed 2287 PNB patients. A total of 1090 received CIP and 1197 received CIP/FOS. Urosepsis incidence with CIP was 1.1% (12/1090) and fell to 0.2% (2/1197) with CIP/FOS. Our analysis indicates that CIP/FOS significantly decreased the risk of urosepsis compared to CIP alone (adjusted relative risk [aRR] 0.16; p=0.021). The isolated pathogen was E. coli in 12/14 cases, including seven bacteremias. Among E. coli cases, seven strains were CIP-resistant. Eleven of 12 E. coli, including all CIP-resistant strains, were isolated in patients on CIP alone. One case of B. fragilis bacteremia occurred in the CIP/FOS group. No cases of C. difficile infection were identified in the three months post-PNB. Conclusions: The adoption of CIP/FOS antibiotic prophylaxis significantly lowered the rate of post-PNB urosepsis. Conveniently, this regimen is oral, single-dose, and low-cost.