BACKGROUND & AIMS: Xenin is a 25-amino acid peptide produced by specific endocrine cells of the duodenal mucosa. We investigated whether xenin is expressed in neuroendocrine tumors. METHODS: Seventy-two foregut and midgut neuroendocrine tumors were examined by means of immunohistochemistry, confocal laser microscopy with an antibody against the C-terminus of xenin, and high-pressure liquid chromatography after acidic extraction, assessed by radioimmunoassay. RESULTS: We found xenin-immunoreactive cells in 23 of 26 duodenal neuroendocrine tumors, including gastrinomas, somatostatinomas, and nonfunctioning and enterochromaffin cell tumors. In these tumors, up to 20% of the endocrine cells were xenin immunoreactive, and xenin immunoreactivity was concentrated in secretory granules. Xenin was coexpressed with chromogranin A. We found no xenin expression in gastrin-, somatostatin-, and serotonin-immunoreactive cells. High-pressure liquid chromatography after acidic extraction revealed 497 +/- 285 pmol of xenin per gram of tissue in 5 duodenal gastrinomas. The other neuroendocrine tumors, such as bronchial carcinoids, gastric enterochromaffin-like cell carcinoids, gastric and ileal enterochromaffin cell carcinoids, insulinomas, and gastrinomas of pancreatic origin, did not contain immunoreactive xenin. CONCLUSIONS: Xenin is a peptide marker specific to neuroendocrine tumors of the duodenum. This finding may be useful in tumor classification and in the differential diagnosis of neuroendocrine tumors of the upper gut.