This study evaluated the effectiveness of systemic interferon alfa-nl versus isotretinoin in the treatment of condylomata acuminata. Patients were randomly assigned interferon alfa-nl, 5 million units, subcutaneously daily for 2 weeks then twice weekly for 4 weeks, or isotretinoin, 1 mg/kg by mouth daily for 6 weeks. Seventeen otherwise healthy men with histologically confirmed condylomata acuminata refractory to standard treatment completed 6 study weeks. Five of nine men (56%) treated with interferon alfa-nl had an objective clinical response (greater than or equal to 50% clearance of baseline disease), with one patient clearing completely. None of the patients treated with isotretinoin alone had an objective response (p = 0.009). Those whose clearing was incomplete with interferon alone were then assigned to interferon therapy three times weekly in combination with daily isotretinoin for 6 weeks, and those receiving isotretinoin were switched to interferon three times weekly for 6 weeks. There was continued clearing in all patients in the combination treatment group but in only three of seven in the sequential treatment group. Side effects were common and generally predictable for each drug but were generally not exacerbated when interferon and isotretinoin were used in combination. Parenteral interferon alfa-nl is an effective alternative treatment modality for patients with refractory condylomata acuminata.