Hypoxemia occurs during routine hemodialysis and may contribute to morbidity, but its cause is not well understood. We reasoned that patients with COPD would be more vulnerable to abnormalities in gas exchange with dialysis. Thus, to investigate the cause of dialysis-related hypoxemia, we measured gas exchange in a group of stable dialysis patients with normal pulmonary function (n = 6) and a group of dialysis patients with COPD (n = 6). Measurements were made predialysis, at 1 h, and postdialysis with both acetate and bicarbonate dialysates. Acetate dialysis decreased PaO2 in normal and COPD patients at 1 h and postdialysis. Acetate-induced hypoxemia was associated with reduced respiratory CO2 excretion and hypoventilation but PaCO2 did not change. This decrease in CO2 excretion resulted from CO2 fixation during acetate metabolism and modest CO2 loss across the dialyzer. Hypoxemia occurred only postdialysis with bicarbonate dialysate in normal and COPD patients. An increased P(A-a)O2 occurred postdialysis with both dialysates, and was most consistently observed in the COPD patients. In summary, at least two mechanisms contribute to dialysis hypoxemia. With acetate dialysate, alveolar hypoventilation from CO2 unloading occurs at 1 h and postdialysis due to acetate metabolism. However, abnormalities in ventilation/perfusion contribute to postdialysis hypoxemia observed with both dialysates. In addition, the decrement in PaO2 associated with dialysis is similar in normal and COPD patients, although preexisting COPD makes postdialysis changes more apparent.