The muscle pump and muscle vasodilatory mechanims are thought to play important roles in increasing and maintaining muscle perfusion and cardiac output (Q) during exercise, but their actual contributions remain uncertain. To evaluate the role of the skeletal muscle pump and vasodilatation on cardiovascular function during exercise, we determined leg and systemic haemodynamic responses in healthy men during (1) incremental one-legged knee-extensor exercise, (2) step-wise femoral artery ATP infusion at rest, (3) passive exercise (n=10), (4) femoral vein or artery ATP infusion (n=6), and (5) cyclic thigh compressions at rest and during passive and voluntary exercise (n=7). Incremental exercise resulted in progressive increases in leg blood flow (LBF 7.4±0.7 l min^-1), cardiac output (Q 8.7±0.7 l min^-1), mean arterial pressure (MAP 51±5 mmHg), and leg and systemic oxygen delivery and VO₂. Arterial ATP infusion resulted in similar increases in Q, LBF, and systemic and leg oxygen delivery, but central venous pressure and muscle metabolism remained unchanged and MAP was reduced. In contrast, femoral vein ATP infusion did not alter LBF, Q or MAP. Passive exercise also increased blood flow (LBF 0.7±0.1 l min^-1), yet the increase in muscle and systemic perfusion, unrelated to elevations in aerobic metabolism, accounted only for 5% of peak exercise hyperaemia. Likewise, thigh compressions alone or in combination with passive exercise increased blood flow (LBF 0.5-0.7 l min^-1) without altering Q, MAP or VO₂. These findings suggest that the skeletal muscle pump is not obligatory for sustaining venous return, central venous pressure, stroke volume and Q or maintaining muscle blood flow during one-legged exercise in humans. Further, its contribution to muscle and systemic peak exercise hyperaemia appears to be minimal in comparison to the effects of muscle vasodilatation.