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Peak oxygen uptake (VO2peak) of patients on maintenance hemodialysis is very low. Exercise training performed during, or “on” dialysis, and at other times, “off” dialysis, both improve VO2peak. Equivalence of these approaches has not been shown, nor have the physiologic factors limiting VO2peak been clarified in these patients. We hypothesized that hemodialysis docs not acutely alter the cardiovascular response to peak exercise, and further that anemia and a low peak heart rate limit VO2peak. Ten patients with end-stage renal disease (ESRD) performed cycle ergometry to peak exercise. Peak oxygen uptake measured immediately prior to dialysis was compared with predicted values, and with measurements obtained during the second 30 min of dialysis. The determinants of VO2peak were compared with previously reported norms. “Off” dialysis. VO2peak for nine of 10 patients was below the 95% confidence limit for normals. Their cardiovascular response to peak exercise was unchanged by 30–60 min of hemodialysis. Stroke volume was similar to that of normals; however, peak heart rate was 77% of predicted, and hematocrit was 27% (at rest). Peak exercise mixed-venous oxygen content was 3.6 ml O2 ml.dl−1 blood, similar to values reported for athletes. These findings show that up to 1 h of dialysis minimally effects VO2peak, and imply that low oxygen delivery limited VO2peak in these patients.