One hundred seventy-eight patients were enrolled in a placebo-controlled trial to evaluate three interferon-alpha preparations administered parenterally for the treatment of condyloma acuminatum. When all interferon groups were combined and compared with placebo, interferon recipients had greater rates of complete, 75%, 50%, and 25% lesion resolution than did placebo recipients (P = .21, P = .14, P = .02, and P = .02, respectively). Rates of lesion resolution were higher among women than among men, and women were more likely than men to respond to interferon. Virologic measurements in paired lesion biopsies did not correlate with interferon treatment or disease outcome. Although interferon toxicity was observed frequently, no participant withdrew from the study because of side effects, and dosage alterations were not required. Parenterally administered interferon-alpha is more effective than placebo in treating condyloma acuminatum, although rates of complete response are low. Different regimens, including combination therapy, should be evaluated for treatment of this common sexually transmitted disease.