Keratin expression in eight cases of keratoacanthoma was examined immunohistochemically using a panel of seven monoclonal antibodies to either single or a few subsets of keratin polypeptides, and compared with normal surrounding skin to evaluate their cell phenotypes. Six cases of squamous cell carcinoma of the skin were also examined. In outer root sheath cells of normal hair follicles, all the cells were immunopositive with E3, CK8.12 and 312C8-1 antibodies, limited reactivity was seen at the level of sebaceous duct insertion with 34 beta B4, and restricted expression was seen at the early anagen stage with KS-1A3, while all cells were totally immunonegative with RPN1165 and CK4.62. In all eight keratoacanthomas studied, 312C8-1 immunorectivity was seen in peripheral basaloid cells of the endophytic lobules, E3, CK8.12 and 34 beta 4 immunoreactivity was found in centrally located cells with glassy appearance, while RPN1165 and CK4.62 gave no immunoreaction. In one case, glassy type cells were positive with KS-1A3. These results suggest that keratin expression in keratoacanthomas resembles that in the upper part of the outer root sheath cells of the hair follicle, and suggest the possible origin of keratoacanthoma cells from those of the outer root sheath. However, similar keratin expression was found in squamous cell carcinomas of the skin and we were unable to distinguish these two conditions from their keratin reactivity.