Immunity to Toxoplasma gondii critically depends on TNFR type I-mediated immune reactions, but the precise role of the individual ligands of TNFR1, TNF and lymphotoxin-α (LTα), is still unknown. Upon oral infection with T. gondii, TNF−/−, LTα−/−, and TNF/LTα−/− mice failed to control intracerebral T. gondii and succumbed to an acute necrotizing Toxoplasma encephalitis, whereas wild-type (WT) mice survived. Intracerebral inducible NO synthase expression and–early after infection–splenic NO levels were reduced. Additionally, peritoneal macrophages produced reduced levels of NO upon infection with T. gondii and had significantly reduced toxoplasmastatic activity in TNF−/−, LTα−/−, and TNF/LTα−/− mice as compared with WT animals. Frequencies of parasite-specific IFN-γ-producing T cells, intracerebral and splenic IFN-γ production, and T. gondii-specific IgM and IgG titers in LTα−/− and TNF/LTα−/− mice were reduced only early after infection. In contrast, intracerebral IL-10 and IL-12p40 mRNA expression and splenic IL-2, IL-4, and IL-12 production were identical in all genotypes. In addition, TNF−/−, LTα−/−, and TNF/LTα−/−, but not WT, mice succumbed to infection with the highly attenuated ts-4 strain of T. gondii or to a subsequent challenge infection with virulent RH toxoplasms, although they had identical frequencies of IFN-γ-producing T cells as compared with WT mice. Generation and infection of bone marrow reconstitution chimeras demonstrated an exclusive role of hematogeneously produced TNF and LTα for survival of toxoplasmosis. These findings demonstrate the crucial role of both LTα and TNF for control of intracerebral toxoplasms.