The activity of natural (leukocyte) interferon alfa in the treatment of condylomata acuminata was assessed in a randomized, double-blind, placebo-controlled, multicenter trial. Interferon alfa (Alferon N Injection) or placebo was injected into lesions twice weekly for up to eight weeks. Eighty-six patients were given interferon alfa, and 72 were given placebo. Eighty-six percent of interferon alfa-treated patients and 89% of placebo-treated patients had received previous therapy for condylomata acuminata. Side effects, usually flulike symptoms, occurred briefly after the injections; if present, they disappeared before the end of the third week of therapy. Treatment completely eliminated warts in 62% of interferon alfa-treated patients compared with only 21% of placebo-treated patients. Natural interferon alfa given intralesionally is an effective and safe treatment even in patients with recurrent or recalcitrant genital warts.