Persistent hypoglycemia in the neonate and young infant usually results from inappropriate, excessive secretion of insulin, or a deficiency of one of the hepatic gluco-regulatory enzymes. Hypoglycemia due to hyperinsulinism, whether associated with nesidioblastosis, islet cell hyperplasia, adenoma or normal islets, may have devastating consequences in this age group and demands recognition and effective treatment. Medical management consisting primarily of frequent feeding, the intravenous infusion of glucose and the administration of glucagon, glucocorticoids, epinephrine, and diazoxide is often ineffective and may be punctuated by repeated episodes of hypoglycemia, convulsions, and central nervous system damage. Although subtotal-total pancreatectomy is effective in restoring blood sugar to normal, almost half of the reported patients are mentally retarded. This may be due in part to unwarranted delays in performing pancreatectomy. Experience with 6 patients undergoing subtotal--total pancreatectomy for intractable hypoglycemia supports the contention that this procedure is effective. A euglycemic state was restored in all 6 patients and there was no evidence of residual central nervous system damage. The spleen should be preserved in view of its importance in maintaining normal immunodefense mechanisms.