To unravel the mechanisms by which maximal oxygen uptake (VO2 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, approximately 5,300 m above sea level). With hypoxia, exercise PaO2 dropped to 31-34 mmHg and arterial O2 content (CaO2) was reduced by 35% (P <0.001). Forty-one percent of the reduction in CaO2 was explained by the lower inspired O2 pressure (PiO2) 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 in VO2 max (a greater fall than accountable by reduced CaO2). Peak cardiac output decreased by 17% (P <0.01), due to equal reductions in both peak heart rate and stroke VOlume (P <0.05). Peak leg blood flow was also lower (by 22%, P <0.01). Consequently, systemic and leg O2 delivery were reduced by 43 and 47%, respectively, with hypoxia (P <0.001) correlating closely with VO2 max (r = 0.98, P <0.001). Therefore, three main mechanisms account for the reduction of VO2 max in severe acute hypoxia: 1) reduction of PiO2, 2) impairment of pulmonary gas exchange, and 3) reduction of maximal cardiac output and peak leg blood flow, each explaining about one-third of the loss in VO2 max.