KEY POINTS: This study analyzed the prognostic value of reserves obtained from cardiopulmonary exercise testing in patients on hemodialysis. Each reserve (cardiac, autonomic, and muscular) was associated with mortality, with muscle reserve having the highest prognostic accuracy. Patients with physical frailty also had a fairly good prognosis if their physiological reserve is preserved by exercise testing. BACKGROUND: Potential impairment of exercise capacity is prevalent even in patients undergoing hemodialysis without frailty. Cardiopulmonary exercise testing (CPET) can detect physiological reserves, such as cardiopulmonary, muscle, and autonomic function. We hypothesized that these indices could accurately determine the prognosis of patients on hemodialysis and analyzed them on the basis of their relationship to frailty. METHODS: In this two-center prospective cohort study of patients on hemodialysis from Japan, patients underwent CPET and physical assessment to evaluate peak oxygen uptake (peak VO RESULTS: Data from 189 patients (median [interquartile range] age: 71 [62-77] years) were analyzed. All CPET indicators showed a consistent nonlinear relationship with all-cause mortality after adjustment: for peak VO CONCLUSIONS: Results showed the fragile aspect of the frailty phenotype in the hemodialysis population and the superior ability of CPET to indicate death risk complementing that aspect.