Study objective: To determine the efficacy and toxicity of intralesionally administered interferons in the treatment of condyloma acuminatum. Design: Randomized, double-blind, and placebo-controlled study. Setting: Outpatient clinics at university medical centers. Patients: Seventy-nine patients with biopsy-proved condyloma acuminatum that was refractory to conventional therapy were enrolled in the study. Interventions: Alpha-2b-, alpha-nl-, and beta-interferons were used. One wart on each patient was injected three times per week for 4 weeks with either 1 x 106 units of interferon or placebo. Measurements and main results: Forty-seven percent of warts injected with interferon resolved completely, compared with 22% of placebo-injected warts (P = 0.009). In addition, more recipients of interferon had a complete resolution of uninjected lesions. No differences in rates of response were noted among the different interferon groups. Approximately one third of interferon-injected warts recurred, compared with none of four placebo-injected warts. Intralesionally administered interferon was nontoxic and well tolerated, although transient pain on injection was observed frequently. Conclusions: Intralesional administration of each of these three interferons appears to be useful in treating condyloma acuminatum. However, the frequent recurrence of disease and the failure of many lesions to resolve indicate that different regimens, such as longer courses of therapy or different routes of administration, should be evaluated to maximize beneficial effects of interferon for treating this common sexually transmitted disease.