To investigate the involvement of tenascin, an extracellular matrix glycoprotein, in epithelial growth and malignancy, its specific distribution pattern in the human uterus was examined immunohistochemically. During the proliferative phase of the menstrual cycle, this antigen was found as a sharp band around the endometrial glands. The immunoreactivity persisted until the early postovulatory phase of the menstrual cycle, but was not detectable in the glandular or stromal compartment during this later secretory stage, instead endometrial arterioles were immunostained. In marked contradistinction, when antibodies directed against tenascin were applied to sections of endometrial adenocarcinoma, almost the entire extracellular space stained, whereas the neoplastic cells themselves were nonreactive, whatever the degree of tumor differentiation. In precancerous proliferative lesions of the endometrium, tenascin's presence was variable. It was detectable around some superficial glands demonstrating cystic hyperplasia and around all deeply situated glands at the endometrial/myometrial interface. In cases of adenomatous hyperplaqsia, tenascin immunolocalized throughout the extracellular space of the stroma and the staining intensity was increased as the hyperplasia became more atypical. We therefore conclude that tenascin may be a stromal marker for epithelial proliferative states including those associated with malignancies of the endometrium.