Although an increase in hemoglobin concentration [Hb] in high altitude residents assists oxygen transport, excessive polycythemia ([Hb] ≥ 21 g/100 mL) may cause the syndrome of chronic mountain sickness (CMS). A recent theoretical analysis has suggested that increasing [Hb] above 18 g/100 mL provides no further benefit in oxygen transport at rest. To test this hypothesis, we examined oxygen transport at rest for given arterial oxygen saturations (SaO2, in classes at intervals of 5%) as reported in 206 residents of various altitudes. For SaO2 of 97% versus 87%, [Hb] and a-v oxygen content difference increased (respectively, 14.5 to 17.5 g/100 mL and 4.11 to 5.03 volume %). As SaO2 fell further to 66%, a-v progressively decreased to 3.77 volume %, despite an increase in [Hb] to 24.2 g/100 mL. Over the SaO2 range of 97% to 66%, the a-v difference changed little (-8%) compared to other subjects made acutely hypoxic (-33%), for SaO2 change from 97% to 75%. The results suggest that increasing [Hb] allows greater oxygen extraction (a cardiac output sparing effect), which is maximal at SaO2 of 87% and a [Hb] of 17.5 g/100 mL. For more severe hypoxemia, even to SaO2 of 66%, both increasing [Hb] and increasing output are utilized for oxygen transport. © Mary Ann Liebert, Inc.