Energy expenditure (EE) during treadmill walking under normal conditions (normobaric normoxia, 21% O ) and moderate hypoxia (13% O ) was measured. Ten healthy young men and ten healthy young women walked on a level (0°) gradient a range of speeds (0.67-1.67 m s ). During walking, there were no significant differences in reductions in arterial oxygen saturation (SpO ) between the sexes. The hypoxia-induced increase in EE, heart rate (HR bpm) and ventilation (Formula: see text L min ) were calculated. Using a multivariate model that combined EE, Formula: see text, and HR to predict ΔSpO (hypoxia-induced reduction), a very strong fit model both for men (r  = 0.900, P < 0.001) and for women was obtained (r  = 0.957, P < 0.001). The contributions of EE, VE, and HR to ΔSpO were markedly different between men and women. Formula: see text and EE had a stronger effect on ΔSpO in women (Formula: see text: 4.1% in women vs. 1.7% in men; EE: 28.1% in women vs. 15.8% in men), while HR had a greater effect in men (82.5% in men and 67.9% in women). These findings suggested that high-altitude adaptation in response to hypoxemia has different underlying mechanisms between men and women. These results can help to explain how to adapt high-altitude for men and women, respectively.