During exercise in humans, the alveolar-arterial O(2) tension difference ((A-a)DO(2)) increases with exercise intensity and is an important factor determining the absolute level of oxygen binding to hemoglobin and therefore the level of systemic oxygen transport. During exercise in hypoxia, the (A-a)DO(2) is accentuated. Using the multiple inert gas elimination technique it has been shown that during exercise in acute hypoxia the contribution of ventilation-perfusion inequality to (A-a)DO(2) is rather small and in the absence of pulmonary edema intrapulmonary shunts can be ruled out. This implies that the main mechanism limiting pulmonary gas exchange is diffusion limitation. It is presumed that an elevation of cardiac output during exercise in acute hypoxia should increase the (A-a)DO(2). However, no studies have examined how variations in cardiac output independently affect pulmonary diffusion with increases in exercise intensity. We have consistently observed that during steady-state, submaximal (100-120 W) exercise on the cycle ergometer in hypoxia the lung can accommodate an increase in cardiac output of approximately 2 L x min(-1) without any significant effect on pulmonary gas exchange. This result contrasts with the predicted effect of cardiac output on (A-a)DO(2) using the model of Piiper and Scheid, and thus indicates that an elevation of cardiac output is not necessarily accompanied by a reduction of mean transit time and (or) diffusion limitation during submaximal exercise in acute hypoxia. It remains to be determined what is the influence of changes in cardiac output per se on pulmonary gas exchange during high-intensity exercise.