The recently cloned ligand binding component of the type I human interferon-α/β receptor (IFN-α/βR) and its soluble analogue (p40) were characterized. p40 is a potent inhibitor of type I IFNs and antibodies directed against p40 completely block the activity of type I IFNs in human cells. These antibodies immunoprecipitate cellular 102-kDa (major) and 51-kDa (minor) forms of IFN-α/βR. We find that the 51-kDa IFN-α/βR is a disulfide-linked subunit of the 102-kDa IFN-α/βR. Two types of cDNA clones were isolated and sequenced, a 1.5-kb cDNA coding for the transmembrane 51-kDa IFN-α/βR and a 4.5-kb cDNA coding for p40. In addition to ligand binding, IFN-α/βR is directly involved in signaling, because it becomes phosphorylated at Tyr residues on ligand binding and it is physically associated with the cytoplasmic tyrosine kinase JAK1. J. Leukoc. Biol. 57: 712–718; 1995.