The safety and tolerance of interferon alfa-n3 (IFN-αn3) was tested in 20 adults with asymptomatic human immunodeficiency virus type 1 (HIV-1) infection (>400 CD4 lymphocytes/mm3). IFN-αn3 was self-injected three times per week for 3-6 months: 5 patients received 1 mega-IU (MIU)/dose, 10 received 5 MIU/dose, and 5 escalated to their maximum tolerated dose. Subjects were evaluated every 2-4 weeks through 2 months after cessation of treatment. Neuropsychological tests were given at 3-month intervals. Markers of IFN activity, anti-IFN neutralizing antibodies, and antiviral response were measured monthly. IFN-αn3 was safe and well tolerated: Influenza-like symptoms were uncommon, laboratory toxicity was minimal, no adverse neurobehavioral side effects were evident, and no patient developed neutralizing antibodies against IFN. IFN-αn3 induced IFN-specific biologic responses and dose-related antiviral activity against HIV-1. Subjects showed stabilization of CD4 cells for >20 months. IFN-αn3 should be studied in combination with other antiretroviral agents and in persons with more advanced HIV-1 infection.