Objectives: Cardiopulmonary exercise testing (CPX) can detect physiological reserves such as cardiopulmonary, skeletal muscle, and autonomic function, and the combination of these measures can accurately provide prognostic information. However, these prognostic values in patients on hemodialysis (HD) are unknown. Additionally, although physical frailty is prevalent in this population, latent exercise intolerance is frequently observed even in patients without frailty. Thus, the CPX measures may identify risk in this population regardless of the presence or absence of frailty. This study was conducted to clarify these concerns. Methods: HD patients enrolled prospectively underwent CPX and physical assessment to evaluate peak oxygen uptake (peak VO2), a measure of exercise capacity; peak work rate (WR), a measure of muscle function; the ventilatory equivalent for carbon dioxide (VE/VCO2) slope, a measure of cardiac output during exercise; heart rate (HR) reserve, a measure of autonomic function; and physical frailty phenotype (“robust,” “prefrail,” “frail”). Survival was followed for up to 5 years. Results: Data from 195 patients were analyzed. All CPX measures showed a consistent nonlinear relationship with all-cause mortality after adjustment (Table 1). Meanwhile, frailty phenotype was associated with mortality in the traditional model, but the relationship did not hold in the modified model including peak VO2 as a covariate (Table 1). Also, in both subgroups with and without physical frailty, peak VO2 clearly discriminated a high risk of mortality (Figure 1), and furthermore, all CPX measures were independently associated with an increased risk of mortality (P < 0.05). Particularly, peak VO2 (Δ area under the curve [AUC] 0.10 [0.03, 0.17]) and peak WR (ΔAUC 0.09 [0.02, 0.16]) were found to greatly improve the prognostic accuracy of traditional models. Conclusions: Our results reveal the fragile aspect of the frailty phenotype in the HD population and the superior ability of CPX to indicate the risk of death complementing that aspect.