Background <p>The relationship between high-density lipoprotein cholesterol (HDL-C) concentrations and the risk of peritoneal dialysis-related peritonitis (PDRP) remains unclear. We aimed to examine the association between HDL-C concentrations and the risk of new-onset PDRP in patients undergoing maintenance peritoneal dialysis (PD), while investigating potential modifying factors that may influence this relationship.</p> Methods <p>This retrospective cohort study included 512 eligible patients with maintenance PD recruited from January 1, 2010 to December 31, 2020 at the Peritoneal Dialysis Center of Nanfang Hospital. The study outcome was the new-onset PDRP. Cox proportional hazards models were used to examine the association between baseline HDL-C and new-onset PDRP.</p> Results <p>During a median follow-up of 45 months, 156 incident peritonitis cases (30.5%) were recorded. There was a significantly inverse association between HDL-C concentrations and the risk of new-onset PDRP (per SD increment, adjusted HR = 0.67, 95%CI: 0.51, 0.88). Compared with patients with low HDL-C ( &lt; 40 mg/dL), those with normal (40-60 mg/dL) and high (≥60 mg/dL) HDL-C concentrations had a 35% (adjusted HR = 0.65, 95%CI: 0.43, 0.98) and 60% (adjusted HR = 0.40, 95%CI: 0.18, 0.87) lower risk of new-onset PDRP, respectively. The inverse association between elevated HDL-C concentrations and reduced PDRP risk persisted consistently across all examined subgroups, including those stratified by age, sex, BMI, diabetes status, cardiovascular disease, dialysis vintage, total weekly Kt/V, and C-reactive protein concentrations (all <i>P</i>-interaction &gt; 0.05)</p> Conclusion <p>Higher HDL-C concentrations were independently associated with reduced PDRP risk in maintenance PD patients, suggesting HDL-C may serve as a potential protective marker against peritonitis in this population.</p> Clinical trial number <p>Not applicable.</p>