Hepatic cytochrome P-450 content in adaptation to hypobaric hypoxia was studied in three groups of rats and in their respective controls at sea level atmospheric pressure. The experimental groups were as follows: 1) young male and female rats submitted to 4,400 m (simulated altitude) for 6-8 mo, 2) the same animal model of group 1 submitted to 5,500 m (simulated altitude) for a subsequent period of 2-3 mo, and 3) adult males exposed to 5,500 m for 35 days. Hypoxia caused a marked polycythemia in all three groups, body weight loss in males of the three groups and at 5,500 m also in females, whereas liver weight was normal in groups 1 and 2 and slightly decreased in group 3. Cytochrome P-450 content measured in microsomal suspensions of groups 1 and 2 was unchanged. In liver homogenates, cytochrome P-450 content was normal at 4,400 m (group 1) and decreased at 5,500 m (groups 2 and 3). Therefore, endoplasmic reticulum mass, calculated as the ratio of cytochrome P-450 in the homogenates and in the isolated microsomes, was unchanged in group 1 (4,400 m) and decreased in group 2 (5,500 m). The content of antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, measured in liver homogenates of group 3, were markedly decreased (by 40, 30, and 35%, respectively). Results do not support the hypothesis that an increase in cytochrome P-450 content plays a role in adaptation to hypoxia.