OBJECTIVE - Hypoglycemia is a serious complication of therapy for diabetes. Chronic hypoglycemia and the attendant decrease in quality of life have been rationales for advocating pancreas transplantation as an alternative treatment. However, reports have appeared that suggest that as high as 30-50% of pancreas transplant recipients have occasional symptoms of mild hypoglycemia. Therefore, we studied glucose and hormone levels in transplant recipients and healthy control subjects. RESEARCH DESIGN AND METHODS - We studied glucose and hormone levels in transplant recipients reporting frequent symptoms of hypoglycemia (n = 10), transplant recipients without symptoms of hypoglycemia (n = 9), and healthy control subjects (n = 8) after a mixed meal and during a subsequent 24-h modified fast. All transplant recipients were insulin-independent; were receiving prednisone, cyclosporine, and azothioprine; and had functioning grafts with systemic venous drainage. RESULTS - No significant differences were observed in the fasting glucose, insulin, C-peptide, or glucagon levels when comparing the symptomatic with the asymptomatic groups of patients who had undergone successful pancreas transplantation. Similarly, no significant differences were found in the immediate postprandial period after a mixed meal. However, during the subsequent 24-h fast, glucose levels fell lower in the symptomatic than in the asymptomatic group of patients receiving a transplanted pancreas (71 ± 2 vs. 81 ± 2 mg/dl, P < 0.002). During the fast, no significant differences were found in insulin, C-peptide, or glucagon levels when comparing asymptomatic to symptomatic groups. Of 10 symptomatic recipients of pancreas transplantation, 5 reported symptoms of hypoglycemia during the study. In four of these five subjects, the onset of symptoms corresponded to nadirs in serum glucose, which occurred at values 2 SD or more below the mean glucose observed for the control and the asymptomatic pancreas recipient groups. The serum glucose levels at the time of symptoms in these four subjects were 55, 66, 51, and 57 mg/dl. In each of these four subjects, symptoms abated and the glucose levels rose spontaneously without intervention. One of these four subjects had elevated insulin binding activity in his serum consistent with endogenous insulin antibodies. This individual had a serum glucose value of 55 mg/dl at the conclusion of the 24- h fast without symptoms. CONCLUSIONS - Among a group of pancreas transplant recipients reporting frequent symptoms of hypoglycemia, some individuals demonstrated transient, symptomatic postprandial hypoglycemia. With the exception of one recipient with insulin antibodies, no evidence was found for hypoglycemia during fasting. Although postprandial hypoglycemia may occur in some pancreas transplant recipients, it does not appear to be a highly significant clinical problem.