The effects of exposure to simulated altitude on skeletal muscle and on the cardiocirculatory system rhave been studied on awake, conscious, dogs (16-39 kg) at rest and during moderate treadmill exercise at 15% incline. Measurements were obtained in Denver at a PB of 635 mm Hg and after 3 weeks of continuous exposure to a PB of 435 mm Hg using a hypobaric chamber. At both levels of PB the dogs showed marked panting, associated with pulmonary hyperventilation and low PaCO2's (28 mm Hg at 635 and 17 mm Hg at 435 mm Hg). Resting VO2's were high (12.4 and 11.4 ml/min-kg) reflecting the high respiratory outputs. [Hb] and Hct increased significantly after 3 weeks at 435 mm Hg with a 4 mm Hg decrease in P50. Q, HR, SV and systemic blood pressures were normal in both normoxic and hypoxic animals, at rest as well as during exercise. Arterial and mixed venous PO2's decreased in the hypoxic dogs (82 to 56 and 42 to 36 mm Hg, respectively) but arterial O2 content, arterial-venous O2 content difference and systemic O2 transport remained unchanged. Capillary density in the sternothyroid muscle doubled (617 to 1245 cap/mm2) after 3 weeks at a PB of 435, whereas the average muscle fiber diameter decreased about 30%. Calculations indicate that the PO2 in the 'lethal corner' of the muscle fiber is relatively higher in the hypoxic animal because of the decrease in fiber size and intercapillary distances.