The binding characteristics of a genetically engineered consensus interferon with unusually high biologic activity were compared to the characteristics of recombinant interferon-alpha(2). Both interferon-alpha(2), and the consensus interferon produced typical biphasic Scatchard plots, indicating multiple independent binding sites. The consensus interferon, which exhibited a biologic potency more than 10-fold greater than all other type I interferons, also exhibited binding site affinities greater than those for IFN-alpha(2b). In addition, a larger number of high, and low-affinity cell surface sites were recognized by the consensus interferon, resulting in equivalent numbers of sites bound at reduced molar concentrations compared to IFN-alpha(2b). Thus, at any given biologic activity, similar numbers of sites were bound by the consensus interferon and IFN-alpha(2), despite differences in their molar concentrations, No differences in internalization kinetics were identified between the two interferons, indicating that the differences in cell surface binding may be sufficient to produce the differences in biologic activity.