Peripherin is a type III neuronal intermediate filament and its expression is involved in the growth and development of the peripheral nervous systems. Peripherin expression has been reported in cutaneous endocrine carcinomas, but not in rectal well-differentiated endocrine neoplasms (carcinoid tumors). Well-differentiated endocrine neoplasms have been reported to have a relatively high incidence of metastasis, but there is no complete parameter for prediction of their malignant behavior. The aim of the present study was to clarify the expression of peripherin in human fetal and adult rectal mucosae and rectal well-differentiated endocrine neoplasms and the significance of peripherin expression in well-differentiated endocrine neoplasms. Expression of peripherin was studied immunohistochemically in 3 fetal hindgut mucosae, 10 non-neoplastic rectal mucosae, 12 rectal well-differentiated endocrine neoplasms without metastases, and 5 well-differentiated endocrine neoplasms with metastases. Adult rectal mucosal epithelial cells did not have peripherin. However, transient expression of peripherin was detected in the subgroup of epithelial cells of the fetal rectum. Peripherin was demonstrated in all of the rectal well-differentiated endocrine neoplasms without metastases (12/12 cases), but was absent from some of the well-differentiated endocrine neoplasms with metastases (3/5 cases). Constant expression of peripherin in rectal well-differentiated endocrine neoplasms without metastases (12/12) seems to reflect the phenotype of the subpopulation of epithelial cells confined to the fetal rectum. However, loss of its expression was observed in cases with metastases (3/5) and can be regarded as an additional parameter to predict the risk of metastasis in rectal well-differentiated endocrine neoplasms.