BACKGROUND Local skin reactions are common during imiquimod treatment of actinic keratosis (AK). Cyclical application of imiquimod may improve tolerability while maintaining efficacy. OBJECTIVE To assess the tolerability of imiquimod and clearance rate of AK lesions after imiquimod application. METHODS Imiquimod 5% cream was administered three times per week for 4 weeks followed by 4 weeks of rest (cycle 1) to AK lesions on the head. If AK lesions remained visible at the end of cycle 1, a second treatment cycle was instituted. RESULTS Fifty percent (30 of 60) of patients experienced complete clearance of AK lesions, and 75% (30 of 40) of patients experienced partial clearance of AK lesions after imiquimod treatment at the end of cycle 2. Moreover, 77% of patients who achieved complete clearance had no visible AK lesions 12 weeks post-treatment. Imiquimod was well tolerated. CONCLUSION Imiquimod cycle therapy may be a safe and effective treatment option for AK lesions.