Two patients with severe hypoglycemia since birth are described. In both hyperinsulinism was demonstrated during spontaneous hypoglycemic attacks or could be provoked by various tolerance tests. In case I considerable obesity and psychomotor retardation was present at the age of one year whereas in case II weight gain was normal and development unaffected. Immunofluorescence microscopic and electron microscopic examination of the pancreas after subtotal pancreatectomy revealed diffuse islet cell hyperplasia with nesidioblastosis in case I and β-cell nesidioblastosis in case II. The hyperplastic and nesidioblastotic areas consisted mainly of β-cells. In addition, an accumulation of somatostatin producing cells was observed in case I, and some cells were found with ultrastructural signs of both endocrine and exocrine function. In both cases, pancreatic insulin release was inhibited by a prolonged somatostatin infusion. The results of tolerance tests did not allow a diagnosis of the underlying pancreatic lesion. In case II, leucine-sensitive hypoglycemia detected soon after birth, was present even after subtotal pancreatic resection. Therapeutic trials with diazoxide in case I and a leucine-restricted diet in case II were only of temporary benefit. After subtotal pancreatectomy there was clinical improvement in both cases, but case II still needs a leucine-restricted diet. The familial occurrence of persistent hypoglycemia in both cases suggests that β-cell nesidioblastosis may be a hereditary disorder.