When 2–deoxy—D—glucose (2–DG) is injected into mammals, blood glucose increases markedly, but insulin does not. To determine whether the inhibition of insulin is a direct effect of 2–DG on the pancreatic beta cell or is mediated by epinephrine released from the adrenal medulla, plasma IRI response to intravenous glucose (300 mg/kg, IV) was measured in intact or adrenalectomized monkeys after pretreatment with 2–DG (300 mg/kg, IV) or saline. The insulin response to intravenous glucose was significantly less than control in intact monkeys pretreated with 2–DG. After bilateral adrenalectomy, the insulin response to intravenous glucose was not different from control despite pretreatment with 2–DG. The results demonstrate that 2–DG did not have a direct inhibitory effect on the pancreatic beta cell in adrenalectomized monkeys. The results suggest that epinephrine mediated the inhibition of the insulin response to hyperglycemia observed in intact monkeys. (Endocrinology92: 750, 1973)