Interferon-beta (IFN-beta) is biologically unstable under physiologic conditions in vitro and is cleared rapidly from the bloodstream on administration in vivo. In the present study, we demonstrate that a soluble recombinant form of the type I IFN receptor subunit, sIFNAR-2, can neutralize the bioactivity of type I IFNs at high concentrations and, at lower concentrations, causes an enhancement of IFN-beta-mediated antiviral activity. The in vitro enhancement is due to the specific interaction of IFN-beta with sIFNAR-2, followed by dissociation of IFN-beta from the complex over time in culture. In vivo, the serum half-life of IFN-beta is extended from minutes to hours when administered intravenously in mice as a sIFNAR-2-associated complex. Moreover, the antitumor effect of IFN-beta is increased by between 9-fold and 27-fold when injected as an sIFNAR-2-associated complex, as demonstrated by an increase in the mean survival time of immunodeficient mice challenged with human Burkitt lymphoma cell (Daudi) xenografts (sIFNAR-2-complexed vs. free IFN-beta treatment). These results show that on association with sIFNAR-2, IFN-beta is more stable in vitro and exhibits increased efficacy when administered in vivo. Administration as a complex with sIFNAR-2 may, therefore, provide a method of enhancing the delivery and effectiveness of type I IFNs.