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To unravel the mechanisms by which maximal oxygen uptake (V˙o _2 max) is reduced with severe acute hypoxia in humans, nine Danish lowlanders performed incremental cycle ergometer exercise to exhaustion, while breathing room air (normoxia) or 10.5% O₂ in N₂(hypoxia, ∼5,300 m above sea level). With hypoxia, exercise Pa_O2 dropped to 31–34 mmHg and arterial O₂ content (Ca_O2 ) was reduced by 35% (P < 0.001). Forty-one percent of the reduction in Ca_O2 was explained by the lower inspired O₂ pressure (Pi _O2 ) in hypoxia, whereas the rest was due to the impairment of the pulmonary gas exchange, as reflected by the higher alveolar-arterial O₂ difference in hypoxia (P < 0.05). Hypoxia caused a 47% decrease inV˙o _2 max (a greater fall than accountable by reduced Ca_O2 ). Peak cardiac output decreased by 17% (P < 0.01), due to equal reductions in both peak heart rate and stroke volume (P < 0.05 …