Objective Maintenance hemodialysis (MHD) patients face a high risk of mortality. This study aimed to identify factors associated with mortality and assess the survival benefit of hemodialysis combined with hemoperfusion (HD + HP) using HA130/KHA80 cartridges in MHD patients.Methods A single-center retrospective cohort study was conducted at Shanghai Changhai Hospital, enrolling 640 MHD patients treated from January 2015 to December 2023. Clinical data were extracted from electronic medical records and hemodialysis management systems. Patients were stratified into HD alone (n = 419) and HD + HP (n = 221) groups. Univariate and multivariate logistic regression were used to identify factors associated with all-cause mortality. Time-dependent Cox regression (with HP as a time-varying covariate) was applied to evaluate the association between HP exposure and mortality. Propensity score matching (1:1, caliper width = 0.02) was performed based on sex, age, primary renal disease, vascular access, and comorbidities, yielding 173 balanced patients per group. Simon–Makuch curves and Mantel–Byar tests were used for survival analysis.Results Diabetic kidney disease (DKD) was the most common primary renal disease (30.9%). The overall all-cause mortality rate was 54.4%, and cardiovascular disease was the leading cause of death (32.8%). Exploratory logistic regression identified older age, higher red blood cell distribution width (RDW), DKD, and elevated creatine kinase-MB (CK-MB) as factors associated with increased all-cause mortality, while higher chloride (Cl), total protein (TP), prealbumin (PAB), hemoglobin (HB), and HD + HP therapy were associated with lower mortality (all P < 0.05). As the primary analytical approach for time-to-event outcomes, time-dependent Cox regression showed that HP exposure was associated with a 25% reduction in all-cause mortality after adjustment for confounders (HR = 0.75; 95% CI: 0.58–0.98; P = 0.03). After propensity score matching, HD + HP significantly reduced both all-cause mortality (31.2% vs 64.2%) and cardiovascular mortality compared with HD alone (Mantel–Byar test: P = 0.032 and P = 0.003, respectively).Conclusion Cardiovascular disease is the leading cause of death in MHD patients. HD + HP therapy is associated with a reduced risk of all-cause and cardiovascular mortality in MHD patients, supporting its potential as a strategy to improve survival in this high-risk population.