In a recent study of completely sedentary normal young subjects, leg VO2max was reduced by hypoxia in proportion to mean capillary PO2 as F(I)O2 was reduced from 0.15 to 0.12. However, the increase in VO2max from F(I)O2 = 0.15 to 0.21 was less than expected for the increase in mean capillary PO2. This finding has led us to hypothesize that in sedentary subjects breathing room air, VO2max is not limited by O2 supply but rather by oxidative capacity of mitochondria. The present study sought to obtain further evidence for or against this hypothesis in sedentary subjects by assessing leg VO2max (VO2leg) breathing 100% O2, as well as in normoxia and hypoxia. Data from 18 subjects studied at F(I)O2 = 0.12, 0.15, and 0.21 and from six more studied at 0.12, 0.15, and 1.00 were analyzed. In all 24 we measured VO2leg by arterial and venous blood sampling and thermodilution leg blood flow during maximal cycle ergometry at each F(I)O2. VO2leg was not increased by room air or 100% O2 breathing relative to that observed at F(I)O2 = 0.15, but it was reduced while breathing 12% O2. The data at F(I)O2 = 0.12 and 0.15 conformed to the predictions of O2 supply limitation of maximal VO2 as previously. These results confirm and extend our prior observations that in sedentary, as opposed to trained subjects, muscle VO2max is O2 supply limited only in hypoxia.