Objective To compare the clinical efficacy and safety of 2-hour and 4-hour hemoperfusion combined with hemodialysis (HP+HD) in the treatment of patients undergoing maintenance hemodialysis (MHD), and to provide clinical evidence for optimizing toxin clearance strategies in this population. Methods A prospective open-label randomized controlled trial was conducted. Patients receiving MHD at the Blood Purification Center of Zhoupu Hospital Affiliated to Shanghai University of Medicine & Health Sciences from January to December 2025 were enrolled. They were randomly divided into the 2-hour HP+HD group and the 4-hour HP+HD group at a ratio of 1:1 using a random number table. Both groups were treated with SR150 hemoperfusion cartridge in series with HD, with a HP frequency of once every 2 weeks for a continuous 12-week course. The clearance rates of toxins and inflammatory cytokines after a single session, as well as levels of middle-molecular-weight toxins, protein-bound uremic toxins (PBUTs), inflammatory cytokines, dialysis adequacy, and safety parameters after 12 weeks of treatment, were compared between the two groups. Adverse events and cartridge clotting were also recorded. Results Each group enrolled 52 patients. After a single HP+HD session, the 4-hour group showed significantly higher clearance rates than the 2-hour group for indoxyl sulfate (IS) (Z=-1.928, P=0.047), β2‑microglobulin (β2-MG) (Z=2.583, P=0.020), intact parathyroid hormone (iPTH) (Z=2.505, P<0.001), phosphorus (t=-2.726, P=0.009), tumor necrosis factor-α (TNF-α) (Z=-2.931, P=0.003), interleukin-6 (IL-6) (Z=-2.112, P=0.044), and interleukin-1β (IL-1β) (Z=-2.844, P=0.004). After 12 weeks of treatment, the 4-hour group had significantly lower levels of IS,  β2-MG,  iPTH,  TNF-α, IL-6, and IL-1β than the 2-hour group (t=-4.145, P<0.001; t=-2.532, P=0.013; t=-3.312, P=0.030; t=-2.711, P=0.008;  t=-6.858, P<0.001; t=-4.823, P<0.001, respectively). Regarding safety, no statistically significant differences were found between the two groups in post-treatment hemoglobin, red blood cell count, white blood cell count, platelet count, or albumin (t=1.635, P=0.105; t=0.062, P=0.951; t=1.225, P=0.224; t=-0.063, P=0.548; t=0.062, P=0.951). The incidence of cartridge clotting also did not differ significantly between the groups (χ²=0.188, P=0.665).  Conclusion  The 4-hour HP+HD regimen is more effective in clearing middle-and large-molecular-weight toxins and PBUTs in MHD patients, with a favorable safety profile and feasible operation. It may serve as an optimized treatment option for MHD patients.