Systemic interferon has been advocated as an effective therapy for recurrent genital warts. A double-blind, placebo-controlled, multicenter international trial involving 172 patients with recurrent condylomata was conducted using systemic interferon alfa-2a in doses of 3 or 9 MIU three times per week for 4 weeks. The treatment period was followed by a treatment-free follow-up period of 2 months. Complete responders at month 3 were followed up to 9 months or until they had a recurrence, whichever occurred first. The combined rates of complete response (total disappearance of all lesions without appearance of new ones) and major incomplete response (at least a 75% reduction in total lesion area) at 3 months after the commencement of therapy were 34%, 25%, and 30%, respectively, in 166 patients receiving 3 and 9 MIU of interferon alfa-2a and placebo. The recurrence rates at the end of 9 months were 9% in the placebo and 3-MIU groups and 36% in the 9-MIU group. We conclude that systemic interferon alfa-2a administered three times weekly for 4 weeks at doses of 3 and 9 MIU is not effective as monotherapy for genital warts that have recurred after standard ablative therapy.