Adamantinoma of long bones is a rare skeletal tumor of unknown origin with epithelial and fibrous elements. The ill-defined distinction between the two components in some cases earlier led to the assumption that these might be derived from the same (mesenchymal) stem cell. In this study, we investigated the distribution of extracellular matrix components in 21 adamantinomas by immunohistochemistry, to gain information on the interaction between the epithelial and fibrous parts of the tumor. Collagens I and III, and fibronectin were generally present in the (osteo-)fibrous tissue of adamantinoma but lacked in the epithelial aggregates. There was a clear relation between the identification of the epithelial and fibrous components at the histological level, and the staining for basement membrane proteins collagen IV and laminin. Prominent areas with cohesive epithelial growth were surrounded by continuous basement membranes, whereas less distinct epithelial islands contained membrane interruptions or had no surrounding basement membrane at all. Tenascin stained intensely surrounding demarcated epithelial aggregates, but weakly or absent more distantly. Osteofibrous dysplasia (OFD)-like tumors displayed local spicular density or pericellular staining of basement membrane factors in fields of isolated keratin-positive cells. These findings suggest that in adamantinoma individual epithelial cells transform from the osteofibrous tissue and thereafter form clusters of epithelium, as can be recognized in classic adamantinoma. This is in analogy to the development of the glandular component of biphasic synovial sarcoma. The fibrous part of adamantinoma is, however, believed to be of benign nature. These results further substantiate the hypothesis of osteofibrous dysplasia being a potential precursor lesion of adamantinoma.