Patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD) are typically sedentary and functionally limited as a consequence of their condition. The purpose of this study is to test the effect of a lifestyle physical rehabilitation program (The Life Readiness Program) on physical function in patients with ESRD undergoing HD. Physical function was measured by the Kidney Disease Quality of Life Short Form (KDQOL-SF) physical function score (range, 0 to 100). Eighty-two patients were randomly assigned to a 6-month rehabilitation program (intervention; n = 39) or to standard clinical management alone (control; n = 43). The groups were frequency matched by age, sex, ethnicity, and diabetes as the cause of ESRD. General linear modeling of the change in physical function score was used for multivariate analysis. Physical function scores were not different between groups at baseline. Change in physical function score increased significantly in the intervention group compared with the control group when data were adjusted for the matching variables and adequacy of dialysis (3.2, -3.6; P = 0.04). Additionally, the control group reported more problems with work or daily functions because of emotional problems (P: </= 0.05). In this brief 6-month intervention, The Life Readiness Program showed the therapeutic benefit of a lifestyle rehabilitation program on functional outcomes and health-related quality of life for patients with ESRD undergoing hemodialysis.