Summary Background and objectives Infectious complications remain a significant cause of peritoneal dialysis (PD) technique failure. Topical ointments seem to reduce peritonitis; however, concerns over resistance have led to a quest for alternative agents. This study examined the effectiveness of applying topical Polysporin Triple ointment (P 3 ) against mupirocin in a multi-centered, double-blind, randomized controlled trial. Design, setting, participants, & measurements PD patients routinely applied either P 3 or mupirocin ointment to their exit site. Patients were followed for 18 months or until death or catheter removal. The primary study outcome was a composite endpoint of exit-site infection (ESI), tunnel infection, or peritonitis. Results Seventy-five of 201 randomized patients experienced a primary outcome event (51 peritonitis episodes, 24 ESIs). No difference was seen in the time to first event for P 3 (13.2 months; 95% confidence interval, 11.9–14.5) and mupirocin (14.0 months; 95% confidence interval, 12.7–15.4) ( P =0.41). Twice as many patients reported redness at the exit site in the P 3 group (14 versus 6, P =0.10). Over the complete study period, a higher rate per year of fungal ESIs was seen in patients using P 3 (0.07 versus 0.01; P =0.02) with a corresponding increase in fungal peritonitis (0.04 versus 0.00, respectively; P Conclusions This study shows that P 3 is not superior to mupirocin in the prophylaxis of PD-related infections. Colonization of the exit site with fungal organisms is of concern and warrants further study. As such, the use of P 3 over mupirocin is not advocated in the prophylaxis of PD-related infections.