The present studies were undertaken to assess the adrenergic mechanisms by which epinephrine stimulates glucose production and suppresses glucose clearance in man: epinephrine (50 ng/kg per min) was infused for 180 min alone and during either alpha (phentolamine) or beta (propranolol)-adrenergic blockade in normal subjects under conditions in which plasma insulin, glucagon, and glucose were maintained at comparable levels by infusion of somatostatin (100 μg/h), insulin (0.2 mU/kg per min), and variable amounts of glucose. In additional experiments, to control for the effects of the hyperglycemia caused by epinephrine, variable amounts of glucose without epinephrine were infused along with somatostatin and insulin to produce hyperglycemia comparable with that observed during infusion of epinephrine. This glucose infusion suppressed glucose production from basal rates of 1.8 ± 0.1 to 0.0 ± 0.1 mg/kg per min (P<0.01), but did not alter glucose clearance. During infusion of epinephrine, glucose production increased transiently from a basal rate of 1.8 ± 0.1 to a maximum of 3.0 ± 0.2 mg/kg per min (P<0.01) at min 30, and returned to near basal rates at min 180 (1.9 ± 0.1 mg/kg per min). Glucose clearance decreased from a basal rate of 2.0 ± 0.1 to 1.5 ± 0.2 ml/kg per min at the end of the epinephrine infusion (P<0.01). Infusion of phentolamine did not alter these effects of epinephrine on glucose production and clearance. In contrast, infusion of propranolol completely prevented the suppression of glucose clearance by epineprhine, and inhibited the stimulation of glucose production by epinephrine by 80 ± 6% (P<0.001). These results indicate that, under conditions in which plasma glucose, insulin, and glucagon are maintained constant, epinephrine stimulates glucose production and inhibits glucose clearance in man predominantly by beta adrenergic mechanisms.