The substrate exchange of the calf muscles during leg exercise was compared in patients with chronically reduced blood flow and in matched controls. The arteriovenous differences of glucose, lactate, pyruvate, free fatty acids, glycerol, acetoacetate, beta-OH-butyrate, oxygen, and carbon dioxide were analyzed at rest, at the end of two exercise periods at various work loads, and after 10 min of recovery. Calf blood flow was measured with an electrocardiogram-triggered, computerized, strain gauge, venous occlusion plethysmograph. The results indicate that there was increased extraction of oxygen and ketone bodies in patients with reduced blood flow during exercise, whereas the glucose extraction tended to be lower than in controls. The leg respiratory quotient was lower in the patients even at the point of claudicating pain, suggesting oxidation of endogenous fat. The simultaneously elevated lactate release can be explained by local hypoxia in some muscle fiber populations. The findings are discussed in relation to the enzymatic adaptations known to occur in the calf muscle tissue of these patients.