The response elicited by exercise on pulmonary pressure, cardiac output, and arterial oxygen saturation in 35 lifetime residents of high altitude has been studied at high altitude (14,900 feet above sea level), and 22 residents of low altitude have been studied at sea level. A procedure combining cardiac catheterization, arterial cannulation, and spirometry was carried out. The exercise was moderate and was performed in supine position using a bicycle ergometer, the work load being 300 kg-m/min/m2 and the average increase of the oxygen uptake being 4.7 times at sea level and 4.8 times at high altitude. Both at .sea level and at high altitude the cardiac output augmented during exercise proportionally to the increase in oxygen uptake, and thus followed the pattern of response described by other authors. The cardiac output as well as the oxygen intake, for the magnitude of exertion performed in this study, was almost the same at sea level and at high altitude. The cardiac output rose during exercise almost exclusively as a result of an increase in the heart rate, with the stroke volume remaining practically constant. Despite similar increase in cardiac output, the response of pulmonary pressure was smaller for sea-level subjects than for the high-altitude subjects. Increments of mean pulmonary pressure bf nearly 50% and 100% were observed on exercise at sea level and at high altitude, respectively. During exercise the arterial oxygen saturation did not change in the sea-level studies, but decreased significantly in the high-altitude studies. The decrement observed in high-altitude residents is related to a fall in arterial pO2 which at resting conditions is placed on the steep part of the oxygen dissociation curve.