Neuron-specific enolase (NSE) was studied by immunohistochemistry and radioimmunoassay in ten gastroenteropancreatic (GEP) neuroendocrine tumors. Tissue and serum levels of NSE from the same patients were also analyzed. In all cases, NSE was localized by immunohistochemistry as diffuse cytoplasmic staining to neuroendocrine cells. Tissue levels of NSE were elevated in eight of ten cases while the serum level of NSE was elevated only in one patient with a metastatic gastrinoma to the liver. Examination of the distribution of NSE in a wide range of tumors (n = 55) showed that it is relatively specific for neurons and neuroendocrine tumors. Eight of ten tumors analyzed immunohistochemically for nine polypeptide hormones contained more than one hormone. Two of ten tumors with only one hormone were positive for NSE. The clinical syndrome in all cases was related to only one hormone. These results indicate that the immunohistochemical demonstration of NSE is a good general marker for the neuroendocrine system. While tissue levels of NSE in GEP neuroendocrine tumors are generally elevated, the serum levels of NSE may only be markedly elevated with extensive metastatic disease.