OBJECTIVE: To compare the infective complications between two different antibiotic regimens used as prophylaxis for transrectal ultrasound-guided prostate biopsy (TRUSP Bx). PATIENTS AND METHODS: The records of 709 consecutive patients undergoing TRUSP Bx over a period of 20 months at a UK teaching hospital were examined retrospectively. All clinic letters, microbiology reports and admission records were examined for each patient. RESULTS: Within the study period a total of 454 patients received prophylaxis with ciprofloxacin; 11 of these patients (2.4%) developed an infective complication within 4 weeks of the TRUSP Bx. A total of 255 patients received prophylaxis with co-amoxiclav and gentamicin; 33 patients (12.9%) in this group had an infective complication. No cases of Clostridium difficile infection were recorded for any of these patients within 1 month of receiving antibiotics. Re-introduction of the original regimen led to a fall in infective complications. CONCLUSION: Understandable concerns about the development of hospital-acquired infection led to a new protocol for antibiotic prophylaxis which in turn led to a number of patients being put at increased risk of potentially serious infective complications. Antibiotic prophylaxis must reflect tissue penetration, the organisms encountered and their susceptibilities, as well as being based on objective evidence.