Human immunodeficiency virus–positive MSM develop AIN and anal cancer more frequently than HIV-negative MSM, and progression from normal findings or LSIL to HSIL occurs fast.1- 3,5- 8,15,29,30 Therefore, regular anal screening has been recommended for MSM to detect and treat anal dysplasias as early as possible.16,31 Compared with AIN in HIV-negative individuals, AIN in HIV-positive patients is more recalcitrant to therapeutic interventions.3,15,17 Many different approaches, including topical therapies, electrocautery, laser ablation, infrared coagulation, and surgical excision, have been used. Most approaches, however, have not been validated in controlled randomized trials.2,3,15,16 The successful use of imiquimod cream for the treatment of AIN has been described in an HIV-positive man with carcinoma in situ, in a nonimmunocompromised woman with Bowen disease, and, recently by us, in 10 HIV-positive MSM.19,32,33 In the present study, we used imiquimod to treat 28 HIV-positive MSM with histologically confirmed AIN. After 16 weeks of therapy, 17 (77%) of 22 compliant patients and 17 (61%) of all study patients were free of disease by clinical and histologic criteria. Four (22%) of 18 primary imiquimod responders with a follow-up period of at least 5 months had cytologic abnormalities at the end of the observation period, but only 1 patient (6%) developed HSIL. The relapse rate during follow-up compares favorably with the relapse rates in studies in which ablative techniques were used.17,18 Chang et al17 found persistent or recurrent HSIL in 23 (79%) of 29 HIV-positive patients with high-grade AIN who were treated with excision or cauterization, but their duration of follow-up was longer than ours and the mean time to recurrence was 12 months. We had 9 patients with a follow-up period of 12 months or longer; 8 were clinically and cytologically normal at the end of follow-up, and only 1 had developed HSIL/AIN-2. Goldstone et al18 used infrared coagulation to treat 165 high-grade AIN lesions in 68 HIV-positive MSM. Only 28% of the lesions persisted, which is similar to our results. However, 65% of the patients developed new or persistent HSIL within a median follow-up time (217 days) that was similar to the follow-up period in our study. One advantage of imiquimod therapy over ablative therapies could be the induction of an HPV-specific T-cell immunity, as has been shown with imiquimod treatment of condylomas and vulvar intraepithelial neoplasia.11,34 The decrease in HPV DNA load and infecting HPV types during therapy and the persistent low HPV loads in the follow-up period that were seen in our patients could be the result of an imiquimod-induced TH1 response. The TH1 response has also been assumed to be the reason for the decreases in HPV DNA and messenger RNA that have been seen after imiquimod treatment of condylomas.13,34,35 In our study, 3 patients with residual AIN-1 at the end of therapy had complete clearance of their AIN in the follow-up period, a result that further supports this assumption. It is possible that the “end-of-treatment” biopsy specimen should not be obtained in the first week after the last application of imiquimod, as in this study, but, instead, should be obtained a few weeks later to give time for final clearance of dysplasias.