Keratoacanthoma and squamous cell carcinoma are common skin tumors, especially in immunosuppressed transplant recipients, but the distinction between these two types of epidermal neoplasia may be difficult. Sialyl-Tn (Sia-GalNAc-O-Ser/Thr) is a cell surface carbohydrate associated with hyperplasia in squamous epithelium, and correlated with poor prognosis in several human adenocarcinomas. Twenty-seven keratoacanthomas and 29 cutaneous squamous cell carcinomas were examined for the expression of sialyl-Tn and of the Ki67 epitope, the latter a marker for cell proliferation. By immunohistochemistry, basaloid tumor cells at the periphery of tumor nests showed some degree of sialyl-Tn expression in 16 keratoacanthomas (59%), while only three squamous cell carcinomas (10%) showed sialyl-Tn-positive basaloid tumor cells (p<0.001). Keratinized, differentiated tumor cells were more often sialyl-Tn-positive in keratoacanthomas (89%) than in squamous cell carcinomas (31%) (p<0.001). A striking sialyl-Tn-positivity in the basal cell layer was found in a border zone directly adjacent to most tumors of both types (88 and 88%). By immunohistochemical examination of parallel sections and by double immunofluorescence, sialyl-Tn antigen expression was primarily seen in cells that did not express Ki67, although some overlap was present. Keratoacanthomas from transplant recipients did not differ in sialyl-Tn expression compared to those from non-immunosuppressed patients. The results indicate that sialyl-Tn expression is not directly related to cell proliferation, but rather to cellular features of post-mitotic cells, and that sialyl-Tn is not associated with a malignant phenotype. Sialyl-Tn may be linked to tumor regression, as seen in keratoacanthomas.