OBJECTIVE Hepatitis delta virus (HDV) coinfection is frequent in patients infected with human immunodeficiency virus (HIV), and it may cause death independently of the development of full-blown AIDS. In order to evaluate the efficacy and tolerability of interferon alpha in the treatment of hepatitis delta in HIV-infected patients, and to compare them with those observed in anti-HIV-seronegative patients, we carried out an open uncontrolled trial on 21 HIV-uninfected and 16 HIV-infected patients without severe immunodeficiency. METHODS All patients were treated with recombinant interferon alpha 2b (IFN) at doses of 10 million units thrice weekly for 6 months, and 6 million units thrice weekly for an additional 6 months. Patients showing alanine transaminase activity values persistently reduced by at least 50% from basal values received an additional 1-year course of 3 million units thrice weekly. RESULTS Alanine aminotransferase normalization was observed in 19% of HIV-infected and 14% of HIV-uninfected subjects during the first year; in 12% of HIV-infected and in 9% of HIV-uninfected patients during the second year. Twenty-five percent of HIV-infected and 14% of HIV-uninfected patients stopped IFN because of poor compliance or side effects. Two years after stopping interferon treatment, one anti-HIV-seropositive and two anti-HIV-seronegative patients showed complete persistent biochemical, virological and histologic remission. CONCLUSIONS Long-term efficacy and toxicity of IFN treatment seem not to be different in HIV-infected and -uninfected patients with delta hepatitis; given the overall poor rate of long-term response, IFN treatment could be considered only in immunocompetent HIV-HDV-coinfected patients, strictly selected because of rapidly evolving liver disease.