To gain more insight into the differentiation characteristics of the epithelial cells of the adamantinoma of the long bones, we studied the specific keratin immunoreactivity pattern using monoclonal antibodies on 34 primary, recurrent, or metastatic specimens of 22 patients. The results revealed the widespread presence of keratins 14 and 19 in all specimens studied; 74% showed immunoreactivity of keratin 5, and focal staining of keratin 17 was detected in 50%. Keratins 7 and 13 were found in three adamantinoma specimens. This keratin immunoreactivity pattern was independent of histologic subtype, despite marked variety in differentiation pattern, suggesting a common histogenesis for all subtypes of adamantinoma. Furthermore, the pattern was conserved both in local recurrences and in metastasis. The major pattern found in our study differs significantly from other bone and soft tissue tumors with known epithelial characteristics, e.g., synovial sarcomas, chordomas, and epithelioid sarcomas, in that it lacks immunoreactivity of keratins 8 and 18. Our results suggest a basal epithelial cell-like differentiation of adamantinomas.