The cardiac output response to submaximal supine leg exercise was investigated in 10 healthy men who had lived at 3100 m altitude for 4-32 years. Using the direct Fick method for O2, cardiac output was measured at rest and during 4 work loads requiring O2 uptakes of 600-1600 ml/min. These measurements were repeated using exactly the same work loads after the subjects had been at sea level for 10 days. By normal sea-level standards, these men had subnormal cardiac outputs at high altitude, both at rest and during exercise. Cardiac output increased somewhat (8%) at low altitude. Stroke volume increased 15% after 10 days at sea level, but O2 administration at high altitude produced no increase in stroke volume. Neither pulmonary hypertension nor polycythemia was present to influence cardiac output at high altitude. Changes in pulmonary vascular resistance, acid-base balance, sympathetic activity, blood volume, or ventricular-filling pressure did not accoutn for the observed subnormal response. A depressant effect of chronic hypoxia upon the ventricular myocardium could result in reduced myocardial contractile force and stroke volume.