Release of hypoxanthine and phosphate from exercising legs was studied in eight subjects without known obstructive arterial disease and in 20 claudicants. Lower leg blood flow was measured with a thermodilution catheter in the popliteal/distal femoral vein. The catheter allowed blood sampling from the calf before, during and after exhaustive exercise on a bicycle ergometer at a stepwise increasing load. Resting plasma hypoxanthine levels were higher in claudicants than in normal subjects (p less than 0.05). Hypoxanthine concentrations increased 2-4-fold during exercise, amounting to values ten times higher than the resting levels 5 and 10 min post exercise, in the venous effluent of the normal legs. A similar rise was found in the claudicants despite half the exercise intensity at exhaustion. Popliteal venous concentrations of phosphate increased by approximately 25% during exercise without significant differences between the two groups. During exercise the release of hypoxanthine increased 38-fold and of phosphate 21-fold in the normal lower legs, while a ten-fold increase in both metabolites was recorded in the claudicating legs. The study demonstrated a high release of hypoxanthine and phosphate from the human lower leg during rhythmic, exhaustive exercise (with maximal vasodilation). The result is compatible with the assumption that metabolites from the catabolism of adenine nucleotides (adenosine) play a role in the autoregulation of blood flow in human skeletal muscle. Increased plasma hypoxanthine concentrations at rest may indicate peripheral arterial insufficiency.