To assess the adrenergic mechanisms responsible for the effect of epinephrine on glucose production and glucose clearance in man, epinephrine (50 ng/kg/min) was infused in the presence and absence of alpha adrenergic (phentolamine) and beta adrenergic (propranolol) antagonists under conditions when plasma glucose, insulin, and glucagon levels were allowed to vary and when they were clamped by a concurrent infusion of glucose, somatostatin, and insulin. When plasma glucose, insulin, and glucagon were permitted to vary during beta adrenergic blockade, plasma glucose and glucose production increased, respectively, 32% and 42% less and plasma epinephrine concentrations were threefold greater than those during infusion of epinephrine alone; plasma insulin decreased during beta blockade but increased during infusion of epinephrine alone; glucose clearance was comparably suppressed in both instances. When alpha adrenergic blockade was superimposed on beta blockade, the increase in glucose production and the decrease in both plasma insulin and glucose clearance observed during infusion of epinephrine alone was virtually abolished. In contrast, when plasma glucose, insulin, and glucagon were clamped, beta adrenergic blockade completely prevented the suppression of glucose clearance by epinephrine and inhibited the stimulation of glucose production by epinephrine by 80% whereas alpha adrenergic blockade had no effect on either of these parameters. These results indicate that in man, epinephrine increases glucose production and decreases glucose clearance by both alpha and beta adrenergic actions. The alpha adrenergic effects could be accounted for by inhibition of insulin secretion. The mechanism for the beta adrenergic effects remains to be defined but may reflect a direct action of epinephrine on hepatic and peripheral tissues.