The cardiovascular and metabolic responses to supine leg exercise were measured in 9 healthy subjects (controls) and in 19 subjects with two primary forms of autonomic failure (11 with peripheral sympathetic denervation [pure autonomic failure; PAF], 8 with central sympathetic failure [multiple system atrophy; MSA]). With exercise, blood pressure increased in controls and fell markedly in subjects with PAF and MSA. Blood pressure returned to baseline in controls, but remained low in the PAF and MSA groups. With exercise, heart rate increased more in controls than the PAF and MSA groups. Resting plasma noradrenaline concentrations in controls and in subjects with MSA were similar, but were lower in subjects with PAF. With exercise, plasma noradrenaline concentrations increased in controls and were unchanged in subjects with PAF; there was no significant increase in the MSA group. Resting plasma lactate, pyruvate and lactate/pyruvate ratios were similar in all three groups. With exercise, lactate concentrations increased until 2 minutes post exercise in all groups. Pyruvate concentrations after 9 minutes' exercise were higher in controls than in the PAF group but were similar to the MSA group; thereafter, concentrations increased similarly in all groups. The lactate/pyruvate ratio increased until 2 minutes post exercise in all groups. Resting plasma free fatty acids, and beta-hydroxybutyrate were similar in all groups. Plasma glycerol concentrations in control and MSA subjects were similar; concentrations were lower in PAF subjects. With exercise, plasma free fatty acids and glycerol concentrations remained unchanged in all groups; beta-hydroxybutyrate concentrations decreased less in control subjects than in PAF and MSA subjects. In conclusion, there were similar concentrations of plasma free fatty acids, glycerol and beta-hydroxybutyrate in control, PAF and MSA subjects; this could indicate up-regulation of beta-receptors in AF, or that sympathetic activity plays a smaller role in lipolysis. Plasma lactate and pyruvate concentrations increased similarly in all groups, despite marked differences in BP; this suggested an impairment of production or clearance of lactate in AF. A role for lactate-induced vasodilatation, not compensated for by sympathetic vasoconstriction, remains speculative.