We infused epinephrine, glucagon, and cortisol in combination into health overnight-fasted subjects in doses designed to simulate changes in severe stress. When all three hormones were infused simultaneously, glucose levels rose above 200 mg/dl in spite of a 100-200% increase in plasma insulin. In contrast, infusion of each hormone individually produced either a mild (less than 120 mg/dl) or a transient elevation in the plasma glucose concentration. With the combined hormone infusion, the increment in plasma glucose was 3-fold greater than the sum of the responses to the individual hormones (P less than 0.001). The marked hyperglycemia in this setting is a result of ongoing glucose overproduction which is stimulated by epinephrine and glucagon and sustained by cortisol. Furthermore, epinephrine (and possibly cortisol) inhibited glucose disposal despite concomitant hyperinsulinemia. In contrast to their effects on glucose regulation, the simultaneous infusion of epinephrine, glucagon, and cortisol failed to cause hyperketonemia. We conclude that the combined infusion of epinephrine, glucagon, and cortisol produces a greater than additive hyperglycemic response in normal humans. These data suggest that the clinical occurrence of fasting hyperglycemia in a setting of hypersecretion of multiple antiinsulin hormones (stress hyperglycemia) may result, at least in part, from synergistic interactions among these hormones.