The immunohistochemical typing of cytoplasmic intermediate filaments has proved helpful to the pathologist in classifying poorly differentiated malignant neoplasms. In general, identification of keratin-type intermediate filaments has been associated with epithelial histodifferentiation, but several exceptions to this generalization have been reported in the literature. A recent report identified false-positive immunostaining for keratin in osteosarcomas of the jaws that was attributed to cross-reactivity induced by enzyme digestion of the tissue specimens before immunostaining. Because the jaws are unique in the skeletal system because of their relatively high incidence of intraosseous epithelial neoplasms, false-positive immunoreactions for keratin could complicate differentiating sarcomatoid epithelial neoplasms from poorly differentiated osteosarcomas. To evaluate this possible pitfall in our laboratory, eight osteosarcomas of the jaws were evaluated for keratin immunostaining with polyclonal and monoclonal antibodies on tissue sections that had been enzymatically treated with protease. No immunostaining was demonstrated in these tumors. Repudiation of the usefulness of antikeratin immunohistochemistry for intraosseous jaw tumors was not confirmed with the procedures used in our laboratory.