Although successful pancreas transplantation in humans with type I diabetes mellitus restores glucose-induced insulin secretion, provides freedom from insulin treatment, and normalizes fasting glucose levels, much less is known about its effects on counterregulation of hypoglycemia. To determine whether pancreas transplantation normalizes glucagon secretion and hepatic glucose production (HGP) during hypoglycemia, we performed hyperinsulinemic hypoglycemic clamps in successful recipients of pancreas allografts. Recipients were found to have glucagon secretory responses during hypoglycemia that were similar to those of control subjects (incremental glucagon response: recipients, 147 ± 34 ng/L; control subjects, 161 ± 43 ng/L, NS) but were significantly higher than those of matched subjects with type I diabetes (23 ± 9 ng/L, P < 0.01). HGP rates at the end of 120 min of hypoglycemia were also significantly higher in recipients and control subjects than in subjects with diabetes (pancreas recipients, 1.92 ± 0.33 mg · kg-1 · min-1; control subjects, 2.05 ± 0.18 mg · kg-1 · min- 1; subjects with type I diabetes, 0.58 ± 0.12 mg · kg-1 · min-1). A comparison with a third group of nondiabetic kidney transplant recipients demonstrated that the beneficial effects on glucose counterregulation were a result of pancreas transplantation and not the associated immunosuppressive therapy. We conclude that pancreas transplantation restores hypoglycemia- induced glucagon secretion and HGP, thereby allowing for normalization of glucose recovery from hypoglycemia.