A computer-built, three-dimensional, atomic-level model for human interferon-alpha (IFN-alpha) was constructed. This model was prepared using the primary amino acid sequence of consensus IFN-alpha (IFN-alpha Con1) and the alpha-carbon Cartesian coordinates of murine IFN-beta as a homolog guide to the model building. In agreement with an earlier report from this laboratory, the two domains 29-35 and 123-140 are in close spatial proximity in this model, and may constitute a receptor recognition domain, whereas the region bounded by residues 78-95 is somewhat removed from this region on the molecule and may constitute an alternative active site. Extrapolating from the model, we propose that, of the stretch 123-140, the residues that are exposed are 123, 125, 126, 128-130, and 132-139; and of the stretch 29-35, all are accessible. Additionally, we propose that there may be sufficient complexity in the Type 1 IFN receptor to account for the differential sensitivities between IFN-alpha s and IFN-beta that may be associated with residue differences in the region 78-95, specifically at residues 84, 86, and 87. This model conforms with experimental data that identify specific amino acid residues in human IFN-alpha that either do, or do not, affect the active conformation and biological activities of the molecule.