Isoforms of the transmembrane glycoprotein CD44, which are generated by alternative splicing of nine variant exons, have been implicated in tumor cell adhesion, invasion and metastatic spread and may be indicators of the degree of tumor differentiation. Since little is known about the distribution of CD44 in non-neoplastic neuroendocrine cell types, we systematically investigated 42 samples of tissue from different organs, including the pituitary gland, thyroid, parathyroid, adrenal gland, lung, pancreas, stomach, duodenum, jejunum, ileum, appendix, and colon, immunohistochemically for the expression of CD44 standard and variant exon-encoded gene products (CD44v3, v4, v5, v6, v9). Furthermore, double immunolabeling for CD44 and a variety of peptide hormones was applied to characterize the different neuroendocrine cell types. Our results show that neuroendocrine cells derived from the neuroectoderm lack CD44 immunoreactivity. However, those originated from the endoderm exhibit a variable CD44 immunostaining which is related to their anatomical localization and the degree of differentiation irrespective of the hormone produced. Furthermore, we demonstrate that CD44 positive neuroendocrine cells predominantly express CD44 isoforms of the epithelial type and that hyperplastic clusters of neuroendocrine cells of pancreatic ducts express CD44 most probably as a sign of dedifferentiation.