The morphological abnormalities of the endocrine pancreas that underlie persistent neonatal hyperinsulinemic hypoglycemia (PNHH) and are included under the heading "nesidioblastosis" appear to be heterogeneous. We studied pancreatic specimens of 24 patients by light microscopy and immunocytochemistry in order to classify the changes of the endocrine pancreas and relate them to the therapy applied. Two main forms of nesidioblastosis were recognized: a focal and a diffuse type. Both types occurred with equal frequency. Focal nesidioblastosis was characterized by nodular hyperplasia of islet-like cell clusters, including ductuloinsular complexes and hypertrophied insulin cells with giant nuclei. In nine patients, this lesion was unifocal (including an adenoma-like nodule), while two patients each had two separate foci, and one patient had at least three foci. Diffuse nesidioblastosis involved the entire pancreas; it was distinguished by irregularly sized islets and ductulo-insular complexes, both of which contained distinctly hypertrophied insulin cells. Three pancreases lacked these diagnostic features and thus posed difficult diagnostic problems. From the follow-up data, we conclude that partial pancreatectomy with excision of the diseased focus is the treatment of choice for most patients with focal nesidioblastosis whereas diffuse nesidioblastosis requires near-total pancreatectomy. In two patients who had multifocal and diffuse nesidioblastosis and were treated at the age of 6 and 8 years, respectively, the changes of the endocrine pancreas were comparable with those of the young age group and failed to reveal any signs of maturation.