Background: Chronic mountain sickness (CMS) is characterized by a combination of excessive erythrocytosis, severe hypoxemia, and pulmonary hypertension, all of which affect exercise capacity. Methods: Thirteen patients with CMS and 15 healthy highlander and 15 newcomer lowlander control subjects were investigated at an altitude of 4,350 m (Cerro de Pasco, Peru). All of them underwent measurements of diffusing capacity of lung for nitric oxide and carbon monoxide at rest, echocardiography for estimation of mean pulmonary arterial pressure and cardiac output at rest and at exercise, and an incremental cycle ergometer cardiopulmonary exercise test. Results: The patients with CMS, the healthy highlanders, and the newcomer lowlanders reached a similar maximal oxygen uptake at 32 ± 1, 32 ± 2, and 33 ± 2 mL/min/kg, respectively, mean ± SE (P = .8), with ventilatory equivalents for CO2 vs end-tidal PCO2, measured at the anaerobic threshold, of 0.9 ± 0.1, 1.2 ± 0.1, and 1.4 ± 0.1 mm Hg, respectively (P < .001); arte rial oxygen content of 26 ± 1, 21 ± 2, and 16 ± 1 mL/dL, respectively (P < .001); diffusing capacity for carbon monoxide corrected for alveolar volume of 155% ± 4%, 150% ± 5%, and 120% ± 3% predicted, respectively (P < .001), with diffusing capacity for nitric oxide and carbon monoxide ratios of 4.7 ± 0.1 at sea level decreased to 3.6 ± 0.1, 3.7 ± 0.1, and 3.9 ± 0.1, respectively (P < .05) and a maximal exercise mean pulmonary arterial pressure at 56 ± 4, 42 ± 3, and 31 ± 2 mm Hg, respectively (P < .001). Conclusions: The aerobic exercise capacity of patients with CMS is preserved in spite of severe pulmonary hypertension and relative hypoventilation, probably by a combination of increased oxygen carrying capacity of the blood and lung diffusion, the latter being predominantly due to an increased capillary blood volume. © 2012 American College of Chest Physicians.