Conventional 85% pancreatectomy with splenectomy performed for management of hypoglycemia of neonatal nesidioblastosis has been followed by a dismal prognosis characterized by post-splenectomy sepsis, recurrent hypoglycemia, permanent brain damage, and a high mortality. For our last eight infants we have found it possible to remove at least 95% of the pancreas, preserving the blood supply to the spleen as well as the duodenum. This has permitted satisfactory control of the hypoglycemia and long-term septic complications have been avoided. Follow-up evaluation up to 20 years with successful control of hypoglycemia without progressive brain damage indicates the value of this primary extensive surgical approach.