The effect of glucagon and/or epinephrine on the response to physiologic insulin infusion was evaluated in dogs. Insulin alone produced a transient fall (50%) in glucose output, a threefold rise in glucose clearance, and a decline in plasma glucose, which then stabilized (40--45 mg/dl) afer 1 h. Glucagon infusion prevented the fall in glucose output, but had no effect on insulin-induced elevations in glucose clearance. The fall in plasma glucose was delayed (20 min), but late hypoglycemia was unaltered. Epinephrine infusion blocked the fall in glucose output as well as the insulin-induced rise in glucose clearance and uptake. Thus, while epinephrine and glucagon were equally effective in preventing the fall in glucose output induced by insulin, epinephrine was more effective in preventing insulin-induced hypoglycemia by virtue of its direct inhibitory action on insulin-stimulated glucose utilization. Simultaneous addition of glucagon and epinephrine increased glucose output twofold, suppressed glucose clearance, and caused a 15--30 mg/dl increase in plasma glucose despite ongoing hyperinsulinemia. Our data thus indicate that synergistic hormone interactions may play a role in the counterregulation of insulin hypoglycemia.