This study explored the relationship between metyrapone blockade of endogenous cortisol secretion and the plasma concentration of basal ketone bodies in insulin-dependent diabetic man. Endogenous cortisol secretion was reduced with metyrapone administration (as assessed by a reduction in plasma cortisol and an increase in deoxycortisol concentration) and then simulated with two different schedules of exogenous cortisol administration. Our results demonstrate that administration of metyrapone suppresses plasma cortisol concentration which may then be elevated by the oral ingestion of cortisol. The suppression of endogenous cortisol secretion with metyrapone results in a 50% reduction in basal plasma ketone body concentration. When endogenous cortisol secretion was simulated with the oral administration of 30 mg cortisol, plasma ketone body concentration returned to that concentration observed in the control study. When 60 mg cortisol were administered in divided dosages to the diabetic subjects, hyperketonemia resulted. These results suggest that the normal diurnal variation in plasma cortisol concentration may modulate the basal plasma ketone body concentration in diabetic man. The mechanism of this modulation may be a direct effect of cortisol or may be secondary to cortisol's lipolytic activity and/or its effects on elevating plasma glucagon concentration.