Background: A large proportion (15% to 50%) of the end-stage renal disease population are on peritoneal dialysis (PD). The major limitation is peritonitis, which leads to technique failure, hospitalization, and increased mortality. Oral, nasal, and topical antibiotic prophylaxis; exit-site disinfectants; and other antimicrobial interventions are used to prevent it. This study was conducted to assess what evidence supports these approaches. Methods: The Cochrane CENTRAL Registry, MEDLINE, EMBASE, and reference lists were searched for randomized trials of antimicrobial agents in patients on PD. Two reviewers extracted data on the number of patients with 1 or more episodes and rates of peritonitis and exit-site and tunnel infection, catheter removal and/or replacement, technique failure, antibiotic toxicity, and all-cause mortality. Analysis was by means of a random-effects model, and results are expressed as relative risk (RR) and 95% confidence intervals (CI). Results: Nineteen eligible trials (1,949 patients) were identified. Nasal mupirocin compared with placebo significantly reduced the exit-site and tunnel infection rate (1 trial; 2,716 patient-months; RR, 0.58; 95% CI, 0.40 to 0.85), but not peritonitis rate (1 trial; 2,716 patient-months; RR, 0.84; 95% CI, 0.44 to 1.60). Perioperative intravenous antibiotic therapy compared with no treatment significantly reduced the risk for early peritonitis (4 trials; 335 patients; RR, 0.35; 95% CI, 0.15 to 0.80), but not exit-site and tunnel infection (3 trials; 114 patients; RR, 0.32; 95% CI, 0.02 to 4.81). Conclusion: Based on 1 study, nasal mupirocin reduces exit-site and tunnel infection, but not peritonitis. Based on 4 studies, preoperative intravenous prophylaxis reduces early peritonitis, but not exit-site and tunnel infection. No other antimicrobial intervention has proven efficacy. Given the large number of patients on PD therapy and the importance of peritonitis, the lack of adequately powered randomized trials to inform decision making about strategies to prevent peritonitis is striking. Background: A large proportion (15% to 50%) of the end-stage renal disease population are on peritoneal dialysis (PD). The major limitation is peritonitis, which leads to technique failure, hospitalization, and increased mortality. Oral, nasal, and topical antibiotic prophylaxis; exit-site disinfectants; and other antimicrobial interventions are used to prevent it. This study was conducted to assess what evidence supports these approaches. Methods: The Cochrane CENTRAL Registry, MEDLINE, EMBASE, and reference lists were searched for randomized trials of antimicrobial agents in patients on PD. Two reviewers extracted data on the number of patients with 1 or more episodes and rates of peritonitis and exit-site and tunnel infection, catheter removal and/or replacement, technique failure, antibiotic toxicity, and all-cause mortality. Analysis was by means of a random-effects model, and results are expressed as relative risk (RR) and 95% confidence intervals (CI). Results: Nineteen eligible trials (1,949 patients) were identified. Nasal mupirocin compared with placebo significantly reduced the exit-site and tunnel infection rate (1 trial; 2,716 patient-months; RR, 0.58; 95% CI, 0.40 to 0.85), but not peritonitis rate (1 trial; 2,716 patient-months; RR, 0.84; 95% CI, 0.44 to 1.60). Perioperative intravenous antibiotic therapy compared with no treatment significantly reduced the risk for early peritonitis (4 trials; 335 patients; RR, 0.35; 95% CI, 0.15 to 0.80), but not exit-site and tunnel infection (3 trials; 114 patients; RR, 0.32; 95% CI, 0.02 to 4.81). Conclusion: Based on 1 study, nasal mupirocin reduces exit-site and tunnel infection, but not peritonitis. Based on 4 studies, preoperative intravenous prophylaxis reduces early peritonitis, but not exit-site and tunnel infection. No other antimicrobial intervention has proven efficacy. Given the large number of patients on PD therapy and the importance of peritonitis, the lack of adequately powered randomized trials to inform decision making about strategies to prevent peritonitis is striking.