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Interferon-γ (IFN-γ) exerts pleiotropic effects, including antiviral activity, stimulation of macrophages and natural killer cells, and increased expression of major histocompatibility complex antigens. Mice without the IFN-γ receptor had no overt anomalies, and their immune system appeared to develop normally. However, mutant mice had a defective natural resistance; they had increased susceptibility to infection by Listeria monocytogenes and vaccinia virus despite normal cytotoxic and T helper cell responses. Immunoglobulin isotype analysis revealed that IFN-γ is necessary for a normal antigen-specific immunoglobulin G2a response. These mutant mice offer the possibility for the further elucidation of IFN-γ-mediated functions by transgenic cell- or tissue-specific reconstitution of a functional receptor.