BACKGROUND. The results from four phase III, randomized, vehicle-controlled studies showed that imiquimod 5% cream (imiquimod) was safe and effective in the treatment of actinic keratosis (AK). Patients applied imiquimod or vehicle cream to AK lesions on the face or balding scalp, dosing three times per week or two times per week for 16 weeks. OBJECTIVE. To obtain long-term safety follow-up data and estimate AK recurrence in patients who completely cleared their AK lesions in the treatment area at the 8-week post-treatment visit in the phase III studies. METHODS. One hundred forty-six patients from 30 study centers in the United States were evaluated for clinical evidence of AK, and safety data were collected. RESULTS. After a median follow-up period of 16 months, 24.7% (19 of 77) of the patients administered imiquimod three times per week and 42.6% (23 of 54) of the patients administered imiquimod two times per week had a recurrence of AK (the appearance of at least one AK lesion) in the original treatment area. The median number of AK lesions present was one lesion for both patients receiving imiquimod three times and those receiving imiquimod two times per week compared with a median of six lesions at baseline in the combined three times per week and two times per week phase III studies. There were no long-term safety issues, and the skin quality seen in the imiquimod-treated patients at the end of the phase III studies was maintained. CONCLUSION. One and a half years following treatment, imiquimod continued to provide a long-term clinical benefit in a majority of patients who experienced complete clearance of their AK lesions.