The study investigated the effect of prolonged hypoxia on central [i.e., cardiovascular oxygen delivery (Q̇_aO₂)] and peripheral (i.e., O₂ utilization) determinants of oxidative metabolism response during exercise in humans. To this aim, seven male mountaineers were examined before and immediately after the Himalayan Expedition Interamnia 8000–Manaslu 2008, lasting 43 days, among which, 23 days were above 5,000 m. The subjects showed a decrease in body weight ( P < 0.05) and of power output during a Wingate Anaerobic test ( P < 0.05) and an increase of thigh cross-sectional area ( P < 0.05). Absolute maximal O₂ uptake (V̇O_2max) did not change. The mean response time of V̇O₂ kinetics at the onset of step submaximal cycling exercise was reduced significantly from 53.8 s ± 10.9 to 39.8 s ± 10.9 ( P < 0.05), whereas that of Q̇_aO₂ was not. Analysis of single fibers dissected from vastus lateralis biopsies revealed that the expression of slow isoforms of both heavy and light myosin subunits increased, whereas that of fast isoforms decreased. Unloaded shortening velocity of fibers was decreased significantly. In summary, independent findings converge in indicating that adaptation to chronic hypoxia brings about a fast-to-slow transition of muscle fibers, resulting in a faster activation of the mitochondrial oxidative metabolism. These results indicate that a prolonged and active sojourn in hypoxia may induce muscular ultrastructural and functional changes similar to those observed after aerobic training.