High altitude is among the most challenging environments inhabited by endotherms, in which cold temperature increases metabolic demands while chronic hypoxia constrains aerobic metabolism and can give rise to maladaptive physiological adjustments that lead to pathology. Hypoxic pulmonary hypertension is a common maladaptive response to chronic hypoxia that results from vasoconstriction and remodeling of the pulmonary vasculature, which can induce pulmonary edema, impair gas exchange, and lead to right ventricle hypertrophy. We investigated whether deer mice (Peromyscus maniculatus) native to high altitude have attenuated this maladaptive response to chronic hypoxia and examined the underlying mechanisms involved. Mice from populations native to high and low altitudes were born and raised in captivity, and adults from each population were chronically exposed to warm normoxia or cold hypoxia in a full factorial design. In low-altitude mice, cold hypoxia increased right ventricular systolic pressure (RVSP; a marker of pulmonary artery pressure), thickened pulmonary arteries, and induced right ventricle hypertrophy. Such effects of cold hypoxia were absent or attenuated in high-altitude mice. Ex vivo measurements of vascular function by wire myography showed that pulmonary arteries from high-altitude mice were less sensitive to vasoconstrictors (a-adrenergic agonist) and more sensitive to vasodilators (endothelium-derived nitric oxide) than low-altitude mice. These findings suggest that evolved changes in pulmonary artery function aid in attenuating hypoxic pulmonary hypertension and preserving gas exchange and thus contribute to high-altitude adaptation in deer mice.