Exercise is known to decrease insulin secretion, but the effect on insulin clearance is unclear. We examined the effect of exercise in insulin clearance with euglycaemic insulin clamp in 28 healthy men either 12 h after a marathon run (n = 14) or 44 h after a 2-h treadmill exercise (n = 14), and in seven insulin-dependent diabetes mellitus (IDDM) patients 12 h after a marathon run, and after a resting, control day. During the post-exercise insulin infusion, steady-state plasma insulin concentration was reduced by 9% in healthy men after both types of exercise, and by 16% in the diabetic subjects compared with the control study (P < 0.05 in all). In healthy men, C-peptide concentrations were more than one-third lower during insulin infusion, both after the marathon run (P < 0.001) or treadmill exercise (P < 0.02) compared with the control study. Insulin clearance was significantly increased by exercise both in healthy men (9% P < 0.05) and in IDDM subjects (15%, P < 0.05). After exercise, endogenous insulin secretion in healthy men is reduced and insulin clearance is enhanced both in healthy men and in IDDM patients. Decreased insulin availability may allow enhanced muscle lipid utilization and spare glucose after long-term exercise.