C hronic hypoxia induces polycythemia, pulmonary hypertension, right ventricular hypertrophy, and weight loss. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding proteins that mediate adaptive responses to hypoxia, including erythropoietin, vascular endothelial growth factor, and glycolytic enzymes. Expression of the HIF-1α subunit increases exponentially as O₂ concentration is decreased. Hif1a^–/– mouse embryos with complete deficiency of HIF-1α due to homozygosity for a null allele at the Hif1a locus die at midgestation, with multiple cardiovascular malformations and mesenchymal cell death. Hif1a^+/– heterozygotes develop normally and are indistinguishable from Hif1a^+/+ wild-type littermates when maintained under normoxic conditions. In this study, the physiological responses of Hif1a^+/– and Hif1a^+/+ mice exposed to 10% O₂ for one to six weeks were analyzed. Hif1a^+/– mice demonstrated significantly delayed development of polycythemia, right ventricular hypertrophy, pulmonary hypertension, and pulmonary vascular remodeling and significantly greater weight loss compared with wild-type littermates. These results indicate that partial HIF-1α deficiency has significant effects on multiple systemic responses to chronic hypoxia.J. Clin. Invest. 103:691–696 (1999)