The importance of TNF-α in host defense to the intracellular parasite, Toxoplasma gondii, was investigated in mice lacking both the p55 and p75 receptors for this cytokine. Upon ip infection with the avirulent ME49 strain, knockout mice were capable of limiting acute ip infection, but succumbed within 3 to 4 wk to a fulminant necrotizing encephalitis. Receptor-deficient mice harbored higher cyst burdens and exhibited uncontrolled tachyzoite replication in the brain. The lack of TNF receptors did not adversely affect the development of a type 1 IFN-γ response. In vitro studies with peritoneal macrophages stimulated with IFN-γ and tachyzoites indicated that under limiting concentrations of IFN-γ, nitric oxide-mediated toxoplasmastatic activity is TNF-α dependent. However, this requirement is overcome by increasing the dose of IFN-γ. Furthermore, both ex vivo and in vivo studies demonstrated that inducible nitric oxide synthase induction in the peritoneal cavity and brain is unimpaired in receptor-deficient mice. Thus, TNF-dependent immune control of T. gondii expansion in the brain involves an effector function distinct from inducible nitric oxide synthase activation.