The growth factor-and phorbol ester-inducible prostaglandin H synthase (PGHS)-2 has been found to be constitutively overexpressed in epidermal tumors generated by the initiation-promotion protocol in murine skin, whereas the expression of PGHS-1 does not change under these conditions. In this paper we report the intra-tumor distribution of the aberrantly expressed PGHS-2 and the cancer chemopreventive activity of a specific PGHS-2 inhibitor. By immunohistochemical methods using isoenzyme-specific antibodies, we found that the PGHS-1 protein was expressed in keratinocytes and Langerhans cells dispersed throughout the epithelial part of papillomas and squamous cell carcinomas and in inflammatory infiltrates occasionally seen in these tumors. A uniform pattern of PGHS-2 expression was observed in the basal keratinocytes of papillomas and in the follicular keratinocytes of carcinomas. In addition, Langerhans cells as well as tumor-associated inflammatory infiltrates exhibited PGHS-2-specific immunoreactivity. PGHS-2-catalyzed prostaglandin synthesis stimulated by the phorbol ester 12-O-tetradecanoylphorbol-13 acetate (TPA) in mouse epidermis in vivo was dose-dependently suppressed by topical administration of SC-58125, a specific PGHS-2 inhibitor. TPA-induced edema formation, epidermal DNA synthesis, and mitotic activity were not impaired by SC-58125 applied at a dose that inhibited TPA-induced prostaglandin E 2 synthesis. However, the repetitive epicutaneous administration of SC-58125 substantially and significantly suppressed papilloma development. Malignant progression of papillomas was slightly retarded by the drug. These results indicate that aberrant expression of PGHS-2 in epidermal tumors may be a relevant target for prevention of epidermal cancer development in experimental animals and that the PGHS-2specific inhibitor SC-58125, which is a potent inhibitor of tumor promotion in mouse skin, may be important for cancer chemoprevention in humans as well.