Objective <p>Patients receiving maintenance hemodialysis (MHD) experience a high mortality burden, with cardiovascular disease remaining a major cause of death. This study aimed to evaluate the association between adjunctive hemoperfusion combined with conventional hemodialysis (HD + HP) and long-term survival outcomes in patients receiving MHD.</p> Methods <p>This single-center retrospective cohort study was conducted at Shanghai Changhai Hospital. Patients with end-stage renal disease who received MHD between January 2015 and December 2023 were retrospectively identified from the center’s hemodialysis records. Among the 640 eligible patients, 419 (65.5%) received HD during the study period, whereas 221 (34.5%) received adjunctive HP in addition to HD. HP exposure was modeled as a time-varying covariate in a multivariable time-dependent Cox proportional hazards model to account for treatment timing. A marginal structural model (MSM) using stabilized inverse probability of treatment weighting was further constructed to address measured time-dependent confounding. Propensity score matching was performed as a sensitivity analysis using 1:1 nearest-neighbor matching without replacement, with a caliper width of 0.02. Survival outcomes in the matched cohort were evaluated using Simon–Makuch curves and Mantel–Byar tests.</p> Results <p>Among the 640 included MHD patients, the median age was 67.5 years, 66.9% were male, and the median dialysis vintage was 48.0 months. During follow-up, 348 patients died, corresponding to all-cause mortality proportion of 54.4% in the study sample. Diabetic kidney disease was the most common primary renal disease (30.9%), followed by chronic glomerulonephritis (29.4%) and hypertensive nephropathy (18.6%). Among the 348 deaths, cardiovascular disease was the leading cause of death (32.8%), followed by multiple organ dysfunction syndrome (21.6%). In both the multivariable time-dependent Cox model and the MSM, HD + HP was consistently associated with a lower risk of all-cause mortality compared with HD, with HRs of 0.69 (95% CI, 0.52–0.90; <i>P</i> = 0.009) and 0.73 (95% CI, 0.55–0.97; <i>P</i> = 0.030), respectively. After 1:1 propensity score matching, 173 patients remained in each group with improved baseline balance. In the propensity score-matched cohort, Simon-Makuch analyses further supported a protective association of HD + HP with all-cause and cardiovascular mortality compared with HD (Mantel-Byar test, <i>P</i> = 0.032 and <i>P</i> = 0.003, respectively).</p> Conclusion <p>In this single-center retrospective cohort of patients receiving MHD, cardiovascular disease was the leading cause of death. HD + HP therapy was associated with lower all-cause mortality in time-dependent Cox regression and MSM-based weighted analyses, and with lower all-cause and cardiovascular mortality in propensity score-matched Simon–Makuch analyses. These findings suggest a potential survival benefit of adjunctive HP.</p>