We investigated whether leg and arm skeletal muscle, and cerebral deoxygenation, differ during incremental cycling exercise in men and women, and if women’s lower capacity to deliver O2 affects tissue deoxygenation. Men (n=10) compared to women (n=10), had greater cardiac output, which with greater hemoglobin concentration produced greater absolute (QaO2) and body size-adjusted oxygen delivery (QaO2i) at peak exercise. Despite women’s lower peak QaO2, their leg muscle deoxygenation was similar at a given work rate and QaO2, but less than in men at peak exercise ($δ$tissue saturation index -27.1±13.2% vs. -11.8±5.7%, P<0.01; $δ$[deoxyhemoglobin] 15.03±8.57$μ$M vs. 3.73±3.98$μ$M, P<0.001). At peak exercise, oxygen uptake was associated both with QaO2 and leg muscle deoxygenation (both P<0.01). Arm muscle and cerebral deoxygenation did not differ between sexes at peak exercise. Thus, both high O2 delivery and severe active muscle deoxygenation are determinants of good exercise performance, and active muscle deoxygenation responses are regulated partly in a sex-specific manner with an influence of exercise capacity. © 2013 Elsevier B.V.