Optimal hemodialysis (HD) dose is very important to patients' health and survival, and various indices of adequacy have been incorporated into the current clinical practice to monitor HD efficiency. Exercise during HD could facilitate solute removal; however, it is still unknown whether prolonged intradialytic exercise could further improve HD efficiency. Ten stable "high-functioning" HD patients volunteered to participate. The patients were studied under two scenarios during HD: 1) supine exercise (cycling) for 3 hours at 40% of maximum exercise capacity and 2) no exercise as usual. Blood sampling was acquired pre- and post-HD in both scenarios to calculate the HD efficiency indices. All patients completed the exercise regime with no adverse effects. Rather, all efficiency indices significantly improved in the prolonged exercise scenario, compared with the no-exercise one. In particular Kt/V, urea reduction ratio, and creatinine reduction ratio significantly improved by 20%, 11%, and 26%, respectively, while potassium plasma levels were reduced by 77.5% (p < 0.05). In conclusion, prolonged low-intensity intradialytic exercise improved HD efficiency, with no adverse effects. HD patients should be encouraged to participate in exercise regimes not only for the known long-term benefits regarding their cardiovascular health but also for the acute effect of exercise in the HD adequacy.