Few long-term studies have assessed whether changes in both diet and exercise can improve the health and quality of life (QOL) of hemodialysis (HD) patients. Here we examined whether 12 months of intradialytic protein supplementation and endurance exercise improves physical function, risk of cardiovascular disease (CVD), and QOL in HD patients in a randomized controlled trial (RCT). A total of 138 HD patients (average age 58 years) were assigned for 12 months to control, intradialytic protein, or protein plus exercise groups. The protein and protein plus exercise groups consumed an oral protein supplement (30 grams of whey) three days/week during dialysis. The protein plus exercise group cycled for 30-45 minutes during dialysis treatment. The primary outcome was change in physical function at 12 months, assessed by a shuttle walk test. Secondary outcomes included arterial stiffness, blood pressure, body composition, muscle strength, markers of nutritional status, and QOL. Assessments were conducted at baseline, 6 and 12 months. In total, 101 patients completed the intervention. There were no significant differences between groups in shuttle walk test performance from baseline to 12 months. There were trends for improvements in some secondary measures of physical function and strength in the protein and protein plus exercise groups at six or 12 months, but these did not reach statistical significance. Thus, our trial did not demonstrate significant improvements in markers of physical function, risk of CVD or QOL after one year of intradialytic oral OPS and aerobic exercise training. More comprehensive lifestyle management may be needed to uncover robust improvements in the health and QOL of HD patients.