The role of adenosine in exercise-induced human skeletal muscle vasodilatation remains unknown. We therefore evaluated the effect of theophylline-induced adenosine receptor blockade in six subjects and the vasodilator potency of adenosine infused in the femoral artery of seven subjects. During one-legged, knee-extensor exercise at approximately 48% of peak power output, intravenous (i.v.) theophylline decreased (P < 0.003) femoral artery blood flow (FaBF) by approximately 20%, i.e. from 3.6 +/- 0.5 to 2.9 +/- 0.5 L min(-1), and leg vascular conductance (VC) from 33.4 +/- 9.1 to 27.7 +/- 8.5 mL min-1 mmHg-1, whereas heart rate (HR), mean arterial pressure (MAP), leg oxygen uptake and lactate release remained unaltered (P = n.s.). Bolus injections of adenosine (2.5 mg) at rest rapidly increased (P < 0.05) FaBF from 0.3 +/- 0.03 L min(-1) to a 15-fold peak elevation (P < 0.05) at 4.1 +/- 0.5 L min(-1). Continuous infusion of adenosine at rest and during one-legged exercise at approximately 62% of peak power output increased (P < 0.05) FaBF dose-dependently to level off (P = ns) at 8.3 +/- 1.0 and 8.2 +/- 1.4 L min(-1), respectively. One-legged exercise alone increased (P < 0.05) FaBF to 4.7 +/- 1.7 L min(-1). Leg oxygen uptake was unaltered (P = n.s.) with adenosine infusion during both rest and exercise. The present findings demonstrate that endogenous adenosine controls at least approximately 20% of the hyperaemic response to submaximal exercise in skeletal muscle of humans. The results also clearly show that arterial infusion of exogenous adenosine has the potential to evoke a vasodilator response that mimics the increase in blood flow observed in response to exercise.