Background and significance: Peritoneal dialysis (PD)-related infection is a common serious complication among PD Patients leading to technical failure and a significant cause of morbidity, mortality, and healthcare costs. Yet, prevention strategies of PD-related infection are still unclear. Objective: To compare effectiveness, safety, and cost-utility of chlorhexidine gluconate (CHG)-soaked cloths to mupirocin ointment and exit site usual care with aseptic technique in prevention of PD-related infection. Methods: A double-blind, stratified randomized controlled trial to evaluate effectiveness, safety, and cost-utility; participants were randomized into three arms CHG-soaked cloths, mupirocin, and exit site usual care (normal saline with aseptic technique; control group) in a ratio 1: 1: 1. They were followed through 12 months or until a switch to hemodialysis, or death. The primary outcome was PD-related infection (exit-site and tunnel infection or peritonitis). Time-to-first PD-related infection and longitudinal rates were analyzed by multivariable Cox’s proportional hazards model and Poisson regression, respectively. Secondary outcomes were safety and adverse events related to treatments. Cost-utility analysis alongside a randomized trial will be performed. One year costs were estimated from the patient and societal perspectives and the quality-adjusted life years (QALYs) were calculated based on the responses to the EQ-5D-5L at baseline, 6 and 12 months. Guided by Thai Health Technology Assessment guideline, a markov simulation model was developed to simulate the disease progression of PD treatment. Results were revealed as an incremental cost-effectiveness ratio (ICER) in Thai Baht per QALY gained. Results: Of 184 participants during a study period between June 2016 to August 2018, 62, 61, and 61 were recruited to the CHG-soaked cloths group, mupirocin group, and usual care group, respectively. Sociodemographic and clinical characteristics among 3 groups of patients met inclusion criteria were comparable. For primary outcome, compared with usual care, CHG-soaked cloths decreased the risks of both time-to-first PD-related infection (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.26-0.69; P=0.001) and longitudinal rates (incidence rate ratio [IRR], 0.52; 95% CI, 0.36-0.74; P<0.001). Likewise, mupirocin ointment also resulted in the lower risks of both time-to-first PD-related infection (HR, 0.42; 95% CI, 0.26-0.68; P<0.001) and longitudinal rates (IRR, 0.49; 95% CI, 0.34-0.71; P<0.001). However, the outcomes were not significantly different in the CHG-soaked cloths and mupirocin ointment groups. For secondary outcomes, the incidences of serious adverse events, safety profiles and mortality rates were not significantly different among groups. For the economic analysis, both CHG-soaked cloths group and mupirocin ointment led to improved 0.11 and 0.12 QALYs compared with usual care, with the ICERs for CHG-soaked cloths and mupirocin ointment groups of 130,114 and 149,376 Baht per QALY. Both interventions are cost-effective at the ceiling threshold of 160,000 Baht/QALY gained. Conclusions: The findings of this study reveal that CHG-soaked cloths group and mupirocin ointment can be recommended as routinely for the prevention of PD-related infection in the Thai context. To guide evidence-based best practices, further studies are needed to investigate the long-term effects as well as concerns about bacterial resistance to these interventions.