Our objective was to determine the efficacy and safety of imiquimod 5% cream in the treatment of external genital/perianal warts in an open-label Phase IIIB trial. Patients applied imiquimod 5% cream 3 times per week, for up to 16 weeks. Those who cleared their warts were monitored during a 6-month follow-up period. If their warts recurred, or new warts developed during this time, patients could be re-treated for up to 16 additional weeks. Patients who experienced partial clearance during the initial treatment period entered an extended treatment period of up to an additional 16 weeks. A total of 943 patients from 114 clinic sites in 20 countries participated in this study. Complete clinical clearance was observed in 451/943 (47.8%) patients (intent-to-treat (ITT) analysis) during the initial treatment period, with clearance in an additional 52 (5.5%) patients during the extended treatment period beyond 16 weeks. The overall clearance rate for the combined treatment periods was 53.3%. In a treatment failure analysis, the overall clearance rate was 65.5%; a greater proportion of female patients (75.5%) experienced complete clearance than male patients (56.9%). Low recurrence rates, of 8.8% and 23.0%, were observed at the end of the 3- and 6-month follow-up periods, respectively. The sustained clearance rates (patients who cleared during treatment and remained clear at the end of the follow-up period) after 3 and 6 months were 41.6% and 33.0% (ITT analysis), respectively. Local erythema occurred in 67% of patients. In the majority of patients local skin reactions were of mild to moderate severity. In conclusion, imiquimod 5% cream is an effective self-applied treatment for external genital/perianal warts when applied for up to 16 weeks and is well tolerated for up to 32 weeks.