Perfusion to exercising skeletal muscle is regulated to match O₂ delivery to the O₂ demand, but this regulation might be compromised during or approaching maximal whole-body exercise as muscle blood flow for a given work rate is blunted. Whether muscle perfusion is restricted when there is an extreme metabolic stimulus to vasodilate during supramaximal exercise remains unknown. To examine the regulatory limits of systemic and muscle perfusion in exercising humans, we measured systemic and leg haemodynamics, O₂ transport, and VO₂ and estimated non-locomotor tissue perfusion during constant load supramaximal (SUP) cycling (498±16 W; 110% of peak power; mean±SEM) in addition to both incremental cycling and knee-extensor exercise to exhaustion in 13 trained males. During SUP, cardiac output (Q), leg blood flow (LBF), and systemic and leg O₂ delivery and VO₂ reached peak values after 60-90 s and thereafter levelled off at values similar to or ~6% (P<0.05) below maximal cycling, while upper body blood flow remained unchanged (~5.5 l min^-1). In contrast, Q and LBF increased linearly until exhaustion during one-legged knee-extensor exercise accompanying increases in non-locomotor tissue blood flow to ~12 l min^-1. At exhaustion during cycling compared to knee-extensor exercise, Q, LBF, leg vascular conductance, leg O₂ delivery and leg VO₂ for a given power were reduced by 32-47% (P<0.05). In conclusion, locomotor skeletal muscle perfusion is restricted during maximal and supramaximal whole-body exercise in association with a plateau in Q and limb vascular conductance. These observations suggest that limits of cardiac function and muscle vasoconstriction underlie the inability of the circulatory system to meet the increasing metabolic demand of skeletal muscles and other tissues during whole-body exercise.