Mice lacking the common cytokine receptor gamma-chain (gamma(c)) gene exhibit defective development of NK cells and CD8+ T cells and greatly diminished production of IFN-gamma. Because resistance of SCID mice to Toxoplasma gondii requires IL-12-dependent IFN-gamma production by NK cells, we expected that gamma(c)-deficient mice would succumb rapidly to the parasite. Surprisingly, however, most gamma(c)-deficient mice survived the acute phase of T. gondii infection. As in wild-type mice, this resistance required IL-12 and IFN-gamma; nevertheless, whereas wild-type mice depleted of CD4+ T cells survived, anti-CD4+ treated gamma(c)-deficient mice displayed diminished production of IFN-gamma and all succumbed to acute infection. These data not only reveal a role for CD4+ T lymphocytes in IFN-gamma-dependent host defense but also establish SCID and gamma(c)-deficient mice as powerful complementary tools for assessing the function of NK vs CD4+ T cells in immunopathophysiologic responses.