To investigate the relationship between osteofibrous dysplasia (OFD) and adamantinoma, we analyzed the expression of several proto-oncogene products and extracellular matrix proteins by immunohistochemistry and correlated our results with histological and ultrastructural findings. C-fos and c-jun, but not c-Met, were observed in OFD and in the fibrous and epithelial components of differentiated and classical adamantinomas. Staining for collagen IV, laminin and galectin-3, a laminin binding protein was seen in OFD and around cell nests in adamantinoma. E-, P-, and N-cadherin expression was found in all cases of classical adamantinoma, but not in differentiated adamantinoma or OFD. Osteonectin was detected in both the epithelial and fibrous components of adamantinomas, but osteopontin and osteocalcin were not seen in classical adamantinomas. The results show common expression of a number of oncoproteins and bone matrix proteins in adamantinoma and OFD, some of which are associated with mesenchymal-to-epithelial cell transformation. These findings would be in keeping with the hypothesis that OFD represents a precursor lesion of adamantinoma. Differential expression of a number of bone matrix protein in adamantinoma may also be of diagnostic use in distinguishing these 2 lesions immunohistochemically.