Abstract Background and Aims Peritonitis is a common and serious complication of peritoneal dialysis (PD). A single episode of severe peritonitis or multiple peritonitis episodes frequently leads to diminished peritoneal ultrafiltration capacity, hospitalization, and a switch to hemodialysis. Prevention of infection is the mainstay for the reduction of peritonitis rate. According to the current guidelines, we use nasal antibiotic prophylaxis if patients are identified as nasal Staphylococcus aureus carriers on screening prior to PD beginning. Eradication of S. aureus Regular with nasal mupirocin reduces the rate of exit-site infections but has uncertain effects on the risk of peritonitis. The aim of this study was to evaluate the rate of S. aureus peritonitis in our cohort of patients receiving PD. Method A retrospective single-center study was conducted in a large Italian PD center. We reviewed all cases of bacterial peritonitis from 1999 to 2023. Demographic and clinical characteristics of the patients and microbiological features of the bacteria identified in cultures were extracted from electronic health record. From 2011, all patients were screened before surgery for Methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) with nares swabs. All patients with positive nasal colonization for MSSA and MRSA were treated with nasal mupirocin (nasal ointment twice daily for 5 consecutive days every 4 weeks) until eradication was confirmed by a nasal swab. According to our protocol, from 2011, screening for S. aureus carriage along peritoneal fluid culture was performed in all patients on PD with an episode of peritonitis to verify nasal colonization with S. aureus. The study was approved by the regional ethical committee of Emilia Romagna (507/2021/OSS/AOUMO SIRER ID 2845). Results Overall, 345 cases of peritonitis were reviewed in 214 patients who received peritoneal dialysis. In our center, the rate of peritonitis was 0.23 episodes/patient-year. After the introduction of nasal screening for S. aureus carriage, the episodes of S. aureus peritonitis decreased in frequency (0.0093 episodes/patient-year vs. 0.034 episodes/patient-year) and as absolute number (17.8% vs 3.6%; p = 0.001). No differences were observed in the rate of catheter removal in the two populations (p = 0.99). The age of 109 patients screened for S. aureus carriage was 64.1 ± 17 years. Males accounted for 58.9% and automated PD (APD) was chosen by 66% of the subjects. After an average period of 1.6 years from the start of PD, 7 patients experienced S. aureus peritonitis in the absence of exit-site or tunnel catheter infection. Nasal screening at the time of peritonitis showed that half of them were carriers of S. aureus and half were negative (one patient was not screened). Colonization from S. aureus was found in another 9 patients whose peritonitis was caused by a different type of bacteria (44% S. epidermidis, 33.3% Enterobacteriaceae, 11.1% Acinetobacter, and 11.1% culture-negative peritonitis). Conclusion Our data document that screening for S. aureus, along with other preventive measures, contributes to significantly reducing the rate of S. aureus peritonitis in patients screened and treated for S. aureus carriage at the time of PD start. Routine screening and the use of a mask during connection are required because recolonization occurs frequently in this population.