Background: Keratoacanthomas are characterized by initial rapid enlargement followed by clinical regression. A series of cyclin and cyclin-dependent kinase complexes regulate cell cycle progression. p27^kip inhibits a variety of cyclin–cyclin-dependent kinase complexes in vitro and may act to hold eukaryotic cells in a quiescent state (G0). Objective: We examined expanding and regressing keratoacanthomas for expression of p27^kip. Methods: An immunohistochemical method was used to visualize and count p27^kip-labeled cells in 5 expanding and 15 regressing keratoacanthomas. Results: In normal epidermis p27^kip was found overlying the nuclei of suprabasilar keratinocytes. In expanding keratoacanthoma there was little expression of p27^kip in nuclei of atypical keratinocytes composing the tumor (1.25 ± 2.1 labeled cells per high-power field); in regressing keratoacanthoma the nuclei of most suprabasilar keratinocytes in atypical tumor aggregates contained p27^kip (55.1 ± 28.6 labeled cells per high-power field). The difference was significant at P values of less than .001. Conclusion: The identification of p27^kip in regressing keratoacanthoma but not in expanding keratoacanthoma suggests that p27^kip may be playing a role in promoting regression of keratoacanthoma and is a potential target for pharmacologic intervention. (J Am Acad Dermatol 2000;42:473-5.)