Imiquimod, the first member of a new class of immune response modifiers, is approved for the treatment of external genital and perianal warts. Recently, many clinical trials highlighted the potential of imiquimod as a treatment for other viral infections and cutaneous neoplasms. We report two cases of facial keratoacanthomas (KA) treated with topical 5% imiquimod cream. Patients were successfully cleared of KAs after treatment for 8 weeks. No recurrence occurred after a 1-year follow-up. Despite the fact that KAs are characterized by the potential for spontaneous regression, it is possible that a faster activation of CD4+ lymphocytes, via interferon release and cytokine secretion takes place after imiquimod application leading to KA regression.