Anti-human immunodeficiency virus type 1 (HIV-1) activity was assessed in HIV-1-infected homosexual and bisexual men receiving 18-36 MIU/day of recombinant interferon (IFN)-α2a for Kaposi's sarcoma (KS). The median baseline HIV-1 RNA level was 4.99 log10 copies/mL. Seventeen subjects (68%) showed an RNA decline ≤.5 log10/mL, with a maximum at week 4 (median decline = 1.91, range = 3.64-1.15; P = .0007), after which RNA levels stabilized. Eight subjects (32%) with lower median initial CD4+ T cell counts (60 vs. 350 x 106/L; P = .01) did not show RNA responses. Neither RNA nor KS responses were negatively affected by IFN-α2a dose modifications. Anti-HIV responses of KS responders (n = 15) and nonresponders (n = 10) did not differ. High-dose IFN-α can exert potent anti-HIV activity that is not associated with anti-KS activity.