The US Surgeon General's Report on Physical Activity and Health recommends that people of all ages engage in regular physical activity, and that significant health benefits can be obtained through a moderate amount of physical activity. Physical activity appears to improve health-related quality of life (HRQOL) by enhancing physical functioning in persons compromised by poor health. The Medical Outcomes Study Short Form-36 (SF-36) Health Status Questionnaire was sent to all patients who were 5 years or more post-liver transplantation at the University of California at San Francisco. Additional questions related to coexisting medical conditions and participation in regular physical activity were included. SF-36 scale scores were compared between active and inactive patients. Regression analysis was also performed to determine the contributions of coexisting medical conditions and physical activity to the physical scales of the SF-36 questionnaire. Patients who participated in regular physical activity had significantly higher scores on all physical scales and the physical component scale (PCS). The regression model, which included age, sex, time posttransplantation, retransplantation, recurrence of hepatitis C, number of comorbid conditions, and physical activity participation showed that both the number of comorbid conditions and participation in physical activity were significant independent contributors to the physical functioning scale and PCS. This study indicates that physical activity is related to HRQOL after liver transplantation independent of other coexisting medical conditions.