Interferon (IFN)-alpha subtypes exhibit differences in biological potencies based on their affinity interactions with the IFN receptor subunits, IFNAR1 and IFNAR2. Using available three-dimensional structural information and computational biology, homology models of human IFN-alpha1, human IFN-alpha8, IFN alfacon-1, and murine IFN-alpha4 were derived and docked with the extracellular region of human IFNAR2 to evaluate the behavior of potential interacting residue pairs and characterize the nature of the IFN-IFNAR2 binding interfaces. The data suggest that IFN afacon-1 has 9 optimal interactions with IFNAR2, comprising hydrophobic, electrostatic, and hydrogen bonding. Human IFN-alpha2 exhibits 8 optimal interactions, human IFN-alpha1, 7, and murine IFN-alpha4 exhibits the least number of optimal interactions, at 5. A model of IFNAR1 was generated, taking into consideration the IFNAR1 extracellular domain interaction with cell surface glycosphingolipids, putative ligand interaction residues, and residues stabilizing the structural integrity of IFNAR. IFNAR1 was then docked with the various IFN-IFNAR2 complexes to describe the complete extracellular receptor pocket with bound IFN. These data provide insights into the species specificity of IFN-alphas: residues in murine IFN-alpha4 that preclude strong affinity interactions with human IFNAR because of steric crowding and residues in human IFN-alpha8 that resemble a receptor interactive domain in murine IFN-alpha4, are described.