A subunit of the interferon alpha receptor (IFN alpha R) that confers biologic response to and specific "binding" for IFN alpha 8 has recently been cloned. We have explored the biological consequences of expressing the cloned IFN alpha R subunit in human cells resistant to IFN alpha and in mouse cell lines nonresponsive to human IFN alpha. The expression of the cloned IFN alpha R subunit in the human IFN alpha-resistant K-562 cell line restored sensitivity to the antiviral effect of not only IFN alpha 8 but also IFN alpha 2 and IFN alpha Con1. In mouse L-929 cells the expression of the cloned receptor subunit markedly increased antiviral sensitivity to human type I IFNs. In either human K-562 or mouse L-929 cells these effects were observed without a detectable increase in the binding for any of the subtypes of IFN alpha tested. We propose that the cloned IFN alpha R subunit functions as a transducer subunit for the IFN alpha R. This concept is supported by the finding that the cloned receptor protein, when it is expressed in Cos cells, has an M(r) of 75 kDa, which is different from the main IFN alpha-binding proteins, the alpha and beta subunits of the IFN alpha R. This report also suggests that alterations at the receptor level could be involved in IFN alpha resistance in some cell lines.