The effect of low level, steady-state exercise on pulmonary gas exchange was studied in 7 patients with severe chronic obstructive pulmonary disease and pulmonary hypertension. Exercise led to a significant fall in the arterial PO2 from 76 +/- 10 to 63 +/- 8 mm Hg, a rise in the arterial PCO2 from 56 +/- 6 to 62 +/- 8 mm Hg, and a fall in the mixed venous PO2 from 38 +/- 2 to 32 +/- 2 mm Hg. There was, however, no significant change in the degree of ventilation-perfusion inequality as quantified by the multiple inert gas technique and no evidence that impaired O2 diffusion was playing a role in the increased hypoxemia. We conclude that the worsening hypoxemia with exercise in patients with severe COPD is due to an inadequate ventilatory response (leading to a rise in arterial PCO2) and the impact of a decreased mixed venous PO2 on the end-capillary PO2 of low VA/Q lung units and shunt.