A colony of deer mice sub-species (Peromyscus maniculatus sonoriensis) native to high altitude (HA) has been maintained at sea level for 18-20 generations and remains genetically unchanged. To determine if these animals retain responsiveness to hypoxia, one group (9-11 wk old) was acclimated to HA (3,800 m) for 8 wk. Age-matched control animals were acclimated to a lower altitude (LA; 252 m). Maximal O-2 uptake (over dot (V)O-2max) was measured at the respective altitudes. On a separate day, lung volume, diffusing capacity for carbon monoxide (DLCO), and pulmonary blood flow were measured under anesthesia using a rebreathing technique at two inspired O-2 tensions. The HA-acclimated deer mice maintained a normal over dot (V)O-2max relative to LA baseline. Compared with LA control mice, antemortem lung volume was larger in HA mice in a manner dependent on alveolar O-2 tension. Systemic hematocrit, pulmonary blood flow, and standardized DLCO did not differ significantly between groups. HA mice showed a higher postmortem alveolar-capillary hematocrit, larger alveolar ducts, and smaller distal conducting structures. In HA mice, absolute volumes of alveolar type I epithelia and endothelia were higher whereas that of interstitia was lower than in LA mice. These structural changes occurred without a net increase in whole-lung septal tissue-capillary volumes or surface areas. Thus, deer mice bred and raised to adulthood at LA retain phenotypic plasticity and adapt to HA without a decrement in over dot (V)O-2max via structural (enlarged airspaces, alveolar septal remodeling) and nonstructural (lung expansion under hypoxia) mechanisms and without an increase in systemic hematocrit or compensatory lung growth.