Abstract Background and Aims Intradialytic exercise significantly benefits the physical function of patients undergoing hemodialysis. Prior research into its impact on patient longevity has been constrained by small participant numbers and the lack of a control group. This study investigates the influence of exercise therapy during hemodialysis on patient lifespan in a broad multicenter cohort. Method This forward-looking, multicenter, non-randomized clinical investigation included 17 outpatient clinics from the Kaikoukai Medical Group, recruited between April and December 2018. Participants were voluntarily enlisted in an exercise regimen during their dialysis sessions and segregated into exercising and non-exercising cohorts. The trial was not blinded. The intradialytic regimen comprised stretching and four types of resistance exercises utilizing elastic tubes, conducted thrice weekly. Baseline data encompassing age, gender, stature, baseline weight, duration of hemodialysis treatment, and concurrent diabetic conditions were collected. Additional data regarding hemodialysis, including Kt/V ratio, hemodialysis blood flow rate (QB), dialysate volume (QD), and duration of dialysis, were recorded. Laboratory parameters such as albumin (Alb), calcium (Ca), potassium (K), hemoglobin (Hb), C-reactive protein (CRP), and creatinine (Cr) levels were extracted from medical records. Patient outcomes were monitored until either the occurrence of death or the study's culmination in December 2021. In statistical analyses, missing values were addressed using multiple imputation techniques, and baseline characteristics between groups were compared using an unpaired t-test. Cox proportional hazards regression analysis was employed to examine the relationship between the exercise intervention and survival, adjusting for multiple confounding variables. Three models were constructed for analysis: Model 1 incorporated basic patient data, Model 2 included hemodialysis parameters, and Model 3 involved laboratory data. The study was approved by the Ethical Committee of Nagoya Kyoritsu Hospital. Results The study encompassed 2006 subjects (average age 70.1±0.3 years), with 512 (25.5%) in the exercise group and 1494 (74.5%) in the control group. Initial comparisons indicated that the exercise group had significantly lower average height (160.9±0.3 vs. 159.7±0.4 cm, p=0.03), baseline weight (57.2±0.3 vs. 55.9±0.5 kg, p=0.04), Kt/V ratio (1.59±0 vs. 1.64±0, p=0.01), and QD (494±0.9 vs. 486.8±1.9 ml, p<0.01). Over the median observation period of 25 months, 338 (16.9%) patients, comprising 58 (11.3%) from the exercise group and 280 (18.7%) from the control group, succumbed. Survival analysis revealed a significant association between exercise intervention and mortality reduction, adjusted for confounders in Model 1 (HR 0.6, 95%CI 0.4-0.9, p=0.01), Model 2 (HR 0.55, 95%CI 0.37-0.8, p=0.02), and Model 3 (HR 0.57, 95%CI 0.38-0.87, p=0.01). Conclusion This research is the first to demonstrate a significant association between intradialytic resistance training and improved survival in hemodialysis patients within a multicenter, non-randomized cohort. This relationship remained significant after adjusting for multiple confounding factors, suggesting that incorporating resistance training into standard hemodialysis care could markedly enhance patient survival outcomes.