We used specific antibodies recognizing the receptor 1 (IFNAR1) and the recently cloned receptor 2.2 (IFNAR2.2) chains of the human type I interferon receptor complex to demonstrate that the interferon beta (IFN-beta)-specific receptor-associated phosphoprotein is IFNAR2.2 and not an unknown or additional receptor component. Immunoprecipitation experiments demonstrated that IFNAR2.2 is present in Daudi cells as a cell surface protein of approximately 90-100 kDa, which is tyrosine-phosphorylated and associated with IFNAR1, upon stimulation of cells with IFN-beta. IFNAR2.2 was not detected associated with IFNAR1 in cells stimulated with IFN-alpha, suggesting differences in receptor interaction between the two type I interferons, Both IFNAR1 and IFNAR2.2 undergo tyrosine phosphorylation upon induction by either IFN-alpha or IFN-beta. Therefore, it is unclear as to why IFNAR2.2 is not detectable in IFNAR1 immunoprecipitates in IFN-beta-treated cells. These data suggest that, although IFN-alpha and IFN-beta may utilize similar receptor chains, they interact with IFNAR1 and IFNAR2.2 in different ways.