To determine the roles of glucose counterregulation and the waning of insulin action in the development of posthypoglycemic hyperglycemia (the Somogyi phenomenon), we studied changes in plasma glucose and glucose turnover in five patients with insulin-dependent diabetes mellitus (IDDM) after subcutaneous injection of insulin under conditions in which hypoglycemic glucose counterregulation and the waning of insulin action were allowed to occur or were prevented. In control experiments, in which both glucose counterregulation and insulin waning were allowed to occur, plasma glucose levels decreased from 94 +/- 3 to 47 +/- 7 mg per deciliter and then increased to 289 +/- 20 mg per deciliter at 12 hours because of a marked increase in glucose production. When the waning of insulin action was prevented by insulin infusion, glucose production increased less (P less than 0.01), but marked rebound hyperglycemia still occurred (188 +/- 26 mg per deciliter at 12 hours). When both insulin waning and glucose counterregulation were prevented by infusion of both glucose and insulin, glucose production did not increase, and rebound hyperglycemia did not occur. We conclude that hypoglycemia can cause rebound hyperglycemia in the absence of insulin waning in patients with IDDM, and that this results primarily from an excessive increase in glucose production due to activation of glucose counterregulatory systems.