Interferons (IFN) elicit antiviral and antineoplastic activities by binding to specific receptors on the cell surface. In evaluating the role of IFN as therapeutic agents in AIDS, we investigated the expression of IFNα and γ receptors on peripheral blood mononuclear cells (PBM) from patients with AIDS, ARC, and heterosexual control subjects using radioiodinated IFNα2 and IFNγ. The binding characteristics of the 125I-IFNα and γ to PBM were analyzed to determine receptor numbers and dissociation constants. PBM from controls expressed 498 ± 247 IFNα receptor sites/cell (n = 17). However, eight patients with ARC and seven patients with AIDS had a mean number of IFNα receptor/cell of 286 ± 235 (P < 0.05) and 92 ± 88 (P < 0.001), respectively. This was consistent with elevated levels of serum acid-labile IFNα and cellular 2-5A synthetase activity in patients. Treatment of PBM from the AIDS patients with exogenous IFNα in vitro resulted in minimal 2-5A synthetase induction in comparison to controls. In contrast, the expression of IFNγ receptors in ARC (n = 5) and AIDS (n = 4) patients remained normal. Thus the decrease in IFNα receptor expression and consequent hyporesponsiveness to IFNα raises the question of the usefulness of IFNα therapy in end-stage AIDS. The normal expression of IFNγ receptors in AIDS patients suggests that IFNγ may prove useful in attempts to provide immune reconstitution.