Background <p>Maintenance hemodialysis (MHD) is a well-established modality of renal replacement treatment for patients with end-stage renal disease. Currently, receptor-interacting protein kinase-3 (RIPK3) is considered as a key regulator of inflammation. But its association with mortality in MHD patients remains unclear. Thus, the aim of the present study was to observe the predictive value of plasma RIPK3 for all-cause mortality in patients undergoing MHD with a 4-year follow-up.</p> Methods <p>148 patients undergoing MHD treatment during June 2020 were enrolled. The plasma RIPK3 levels were measured via enzyme-linked immunosorbent assay. Patients were followed up for 4 years to record all-cause mortality until June 2024.</p> Results <p>During the 4-year follow-up period, the total incidence of all-cause mortality was 34.46% (51 of 148 participants). Compared with the survival group, the non-survival group presented significantly greater age, diabetes prevalence, serum hs-CRP, plasma RIPK3, and lower serum albumin levels. Cox multivariate analysis revealed an independent association between plasma RIPK3 levels and all-cause mortality. The optimal cutoff value to predict all-cause mortality in patients receiving MHD was 251.54 ng/mL with the AUC of 0.7 (95% CI 0.61–0.79). Kaplan-Meier estimates showed a significantly greater overall survival probability for patients with RIPK3 concentrations lower than 251.5 ng/mL than for those with RIPK3 concentrations ≥ 251.5 ng/mL (<i>p</i> &lt; 0.001).</p> Conclusion <p>Plasma RIPK3 level may serve as an independent predictor for all-cause mortality in MHD patients.</p>