Cardiovascular strain and hyperthermia are thought to be important factors limiting exercise capacity in heat-stressed humans, however, the contribution of elevations in skin (Tsk) versus whole body temperatures on exercise capacity has not been characterized. To ascertain their relationships with exercise capacity, blood temperature (TB), oxygen uptake (V̇O2), brain perfusion (MCA Vmean), locomotor limb hemodynamics, and hematological parameters were assessed during incremental cycling exercise with elevated skin (mild hyperthermia; HYPmild), combined core and skin temperatures (moderate hyperthermia; HYPmod), and under control conditions. Both hyperthermic conditions increased Tsk versus control (6.2 ± 0.2°C; P < 0.001), however, only HYPmod increased resting TB, leg blood flow and cardiac output (Q̇), but not MCA Vmean Throughout exercise, Tsk remained elevated in both hyperthermic conditions, whereas only TB was greater in HYPmod At exhaustion, oxygen uptake and exercise capacity were reduced in HYPmod in association with lower leg blood flow, MCA Vmean and mean arterial pressure (MAP), but similar maximal heart rate and TB The attenuated brain and leg perfusion with hyperthermia was associated with a plateau in MCA and two-legged vascular conductance (VC). Mechanistically, the falling MCA VC was coupled to reductions in PaCO2, whereas the plateau in leg vascular conductance was related to markedly elevated plasma [NA] and a plateau in plasma ATP These findings reveal that whole-body hyperthermia, but not skin hyperthermia, compromises exercise capacity in heat-stressed humans through the early attenuation of brain and active muscle blood flow.