Energy expenditure (EE) during treadmill walking under normal conditions (normobaric normoxia, 21% O₂ ) and moderate hypoxia (13% O₂ ) 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^-1 ). During walking, there were no significant differences in reductions in arterial oxygen saturation (SpO₂ ) between the sexes. The hypoxia-induced increase in EE, heart rate (HR [bpm]) and ventilation ([Formula: see text] [L min^-1 ]) were calculated. Using a multivariate model that combined EE, [Formula: see text], and HR to predict ΔSpO₂ (hypoxia-induced reduction), a very strong fit model both for men (r²  = 0.900, P < 0.001) and for women was obtained (r²  = 0.957, P < 0.001). The contributions of EE, VE, and HR to ΔSpO₂ were markedly different between men and women. [Formula: see text] and EE had a stronger effect on ΔSpO₂ 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.