Twelve subjects completed a progressive treadmill test to maximal aerobic capacity while breathing air or a 79% helium--21% oxygen gas mixture (HeO2). Metabolic and thermoregulatory responses to work while breathing the two mixtures were compared at rest, 30-40%, 60-70%, and 85-90% of maximal performance, and at maximal effort. Ventilation, ventilatory equivalent, and respiratory rates were increased and oxygen uptakes decreased by breathing HeO2 when the level of work exceeded 85-90% of maximum. Heat loss through the respiratory tract was greater breathing HeO2. The reduction in maximal oxygen uptake is probably due to a reduction in the oxygen cost of breathing a less dense gas. It was not related to a lower body temperature and probably not to O2 transport or circulatory limitation. HeO2 breathing had no effect on maximal mechanical work capacity.