The effect of exercise on pulmonary gas exchange was investigated in 7 patients with pulmonary hypertension resulting from primary pulmonary hypertension or recurrent pulmonary emboli. During supine bicycle exercise averaging 2.4 times baseline O2 consumption there was a significant fall in the arterial PO2 (64 +/- 1.1 to 56 +/- 5.4) and widening of the alveolar-arterial gradient for O2 (50 +/- 4.6 to 62 +/- 5.5). Measurement of the distribution of ventilation-perfusion (VA/Q) ratios by the multiple inert gas technique demonstrated no increase in VA/Q inequality. The increased hypoxemia was due to the fall in the mixed venous PO2 and its impact on the end-capillary blood of the shunt and low VA/Q units present at both rest and exercise. A concomitant shift in the mean VA/Q ratio for the normal lung units mitigated but could not eliminate the fall in the arterial PO2. We conclude that the increased hypoxemia seen during exercise in these patients is due to the widened arterial-venous O2 difference expected with exercise and its effect on the mild VA/Q inequality characteristic of this disorder.