During maximal exercise, ventilation-perfusion inequality increases, especially in athletes. The mechanism remains speculative. We hypothesized that, if interstitial pulmonary edema is involved, prolonged exercise would result in increasing ventilation-perfusion inequality over time by exposing the pulmonary vascular bed to high pressures for a long duration. The response to short-term exercise was first characterized in six male athletes [maximal O2 uptake (V(O2)max) = 63 ml x kg-1 x min-1] by using 5 min of cycling exercise at 30, 65, and 90% V(O2) max. Multiple inert-gas, blood-gas, hemodynamic, metabolic rate, and ventilatory data were obtained. Resting log SD of the perfusion distribution (log SDQ) was normal [0.50 +/- 0.03 (SE)] and increased with exercise (log SDQ = 0.65 +/- 0.04, P < 0.005), alveolar-arterial O2 difference increased (to 24 +/- 3 Torr), and end-capillary pulmonary diffusion limitation occurred at 90% V(O2)max. The subjects recovered for 30 min, then, after resting measurements were taken, exercised for 60 min at approximately 65% V(O2)max. O2 uptake, ventilation, cardiac output, and alveolar-arterial O2 difference were unchanged after the first 5 min of this test, but log SDQ increased from 0.59 +/- 0.03 at 5 min to 0. 66 +/- 0.05 at 60 min (P < 0.05), without pulmonary diffusion limitation. Log SDQ was negatively related to total lung capacity normalized for body surface area (r = -0.97, P < 0.005 at 60 min). These data are compatible with interstitial edema as a mechanism and suggest that lung size is an important determinant of the efficiency of gas exchange during exercise.