Background: Tissue-destructive and more selective cytotoxic therapies are the main methods used to treat actinic cheilitis. A topical immune stimulant, 5% imiquimod cream, has recently been used for treatment of cutaneous epithelial malignancies including squamous cell carcinoma in situ and basal cell carcinoma. Objective: Our aim was to review the results in patients who had been treated for actinic cheilitis with imiquimod cream. Methods: A review identified 15 patients with biopsy-proven actinic cheilitis who had been treated with topical imiquimod 3 times weekly for 4 to 6 weeks. All patients with histories consistent with facial herpes simplex or documented prior facial herpes simplex eruptions were treated with oral valcyclovir, 1 g/d, during imiquimod therapy. Results: All 15 patients showed clinical clearing of their actinic cheilitis at 4 weeks after discontinuation of the topical imiquimod. Sixty percent of the patients experienced a moderate to marked increased local reaction consisting of increased erythema, induration, and erosions or ulcerations, which in some cases continued through the period of therapy. Conclusion: Imiquimod appears to have a role in the treatment of actinic cheilitis. However, the dose and duration of therapy, as well as the long-term efficacy, need to be established; and local reactions are to be expected and may not improve during therapy. (J Am Acad Dermatol 2002;47:497-501.)