OBJECTIVE: To determine whether the combination of systemically administered interferon alpha-2a and ablative surgery for the treatment of genital and/or perianal warts produces a 30% or greater improvement in lasting response rate compared with a control group receiving a combination of placebo and ablative therapy. DESIGN: Randomised, triple-blind, placebo-controlled trial using 1 or 3 MIU of interferon alpha-2a or placebo administered subcutaneously three times weekly for 10 weeks in combination with ablative surgery. SETTING: International, multicentre study in 10 genitourinary medicine clinics. PATIENTS: Two hundred and fifty patients with anogenital warts. MAIN OUTCOME MEASURES: Lasting response at week 38. RESULTS: Standard efficacy analysis at week 38 showed a lasting response in 51% (35/68) of 3 MIU interferon-treated patients, 48% (30/63) of 1 MIU interferon-treated patients and 43% (29/67) of placebo-treated patients. CONCLUSIONS: With the doses and regime described, treatment with interferon alpha-2a in combination with ablative therapy is not significantly superior in the treatment of anogenital warts than placebo and ablative therapy.