Interferon‐α elicits antiviral and immunoregulatory activities by binding to specific receptors on the cell surface. In this study, binding characteristics of interferon‐α to peripheral blood mononuclear cells in patients with chronic hepatitis B virus infection were studied using radioiodinated recombinant interferon‐α2b to determine interferon‐α receptor numbers and dissociation constants. A single class of interferon‐α receptor was demonstrated on peripheral blood mononuclear cells and mononuclear subsets. Peripheral blood mononuclear cells from patients with chronic hepatitis B virus infection (n = 20) and controls (n = 16) expressed a similar number of interferon‐α receptors (484 ± 175 vs. 511 ± 168 sites/cell respectively, p = NS) with a similar dissociation constant (dissociation constant ± 0.2 to 0.7 nmol/L). Expression of interferon‐α receptors was similar in monocyteenriched and lymphocyte‐enriched fractions in both groups. Similar changes were observed in patients receiving α‐interferon therapy. There was no correlation between interferon‐α receptors expression and serum transaminase, serum HBsAg, serum HBV DNA, liver histological findings or the response to interferon‐α therapy. After incubation of lymphocytes in vitro with interferon‐α2b (10 to 1,000 U/ml), interferon‐α receptors number dropped by 42% to 80%, but this was associated with an increase in binding affinity (dissociation constant ≈ 0.05 to 0.15 nmol/L) in both patients and controls. There was significant delay in the initial phase of receptor recovery in the patients with chronic hepatitis B virus infection compared with normal controls (days 1 and 2, p <0.05). These data indicate that interferon‐α receptors are expressed and regulated normally in chronic hepatitis B virus infection and that the variable response to interferon‐α therapy is not due to a variation in interferon‐α receptor. The increase in binding affinity on interferon‐α therapy may be one factor explaining why long‐term interferon‐α therapy is effective despite a decrease in receptor number. (HEPATOLOGY 1991;13:332–338).