Epinephrine (50 ng . kg-1 . min-1) was infused for 120 min in seven normal volunteers alone (combined alpha- and beta-adrenergic stimulation), with propranolol (alpha-adrenergic stimulation), and with propranolol plus phentolamine (alpha-adrenergic blockade superimposed on alpha-adrenergic stimulation). During alpha-adrenergic stimulation, plasma glucose and glucose production increased 32 and 42% less, respectively, than during infusion of epinephrine alone, whereas glucose clearance was suppressed comparably. Plasma insulin decreased during alpha-adrenergic stimulation but increased during infusion of epinephrine alone. Plasma epinephrine was threefold greater during infusion of epinephrine plus propranolol than during infusion of epinephrine alone. When alpha-adrenergic blockade was superimposed on alpha-adrenergic stimulation, the increases in plasma glucose and glucose production as well as the decreases in plasma insulin and glucose clearance observed during alpha-adrenergic stimulation were virtually abolished, whereas plasma epinephrine levels were unaltered. These results indicate that in man epinephrine can cause hyperglycemia via both alpha- and beta-adrenergic stimulation of glucose production and suppression of glucose clearance, either directly or indirectly. alpha-Adrenergic effects on glucose production and clearance may be mediated by inhibition of insulin secretion.