Preliminary observations have indicated the existence of characteristic spectra of gastroenteropancreatic (GEP) neurohormonal peptides in endocrine tumors arising in foregut, midgut, and hindgut derivatives. In order to further explore this feature of GEP endocrine neoplasms, islet cell tumors from 14 patients were studied, as were endocrine tumors of the stomach, duodenum, and upper jejunum from 6, 5, and 2 patients, respectively. All tumors were examined immunohistochemically with antisera raised against islet hormones [insulin, somatostatin, glucagon, pancreatic polypeptide (PP)], peptides of the gastrin family [gastrin, cholecystokinin (CCK)], peptides of the secretin family [secretin, vasoactive intestinal peptide (VIP)], and substance P, neurotensin, leu-enkephalin, beta-endorphin, motilin, calcitonin, and ACTH. In addition, an ultrastructural investigation was made. Whenever possible, the immunohistochemical observations were correlated with the clinical manifestations and with the results of radioimmunochemical determination of GEP neurohormones in the blood. The pattern of immunoreactive neurohormonal peptides and the clinical picture were those to be expected in endocrine tumors arising in foregut derivatives. Some principles are proposed for the classification of GEP endocrine tumors on the basis of their histopathologic growth pattern, their spectrum of neurohormonal peptides, and their clinical manifestations.