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.