The relationship between IFN-gamma and IL-12 in generating innate immune responses and resistance to acute Toxoplasma gondii infection was assessed in T. gondii-exposed IFN-gamma knockout (gko) mice. Gko mice, in contrast to wild-type (wt) animals, rapidly succumbed to infection with either the avirulent ME49 strain or, surprisingly, an attenuated temperature-sensitive mutant strain, ts4. Microscopic examination of peritoneal exudates from infected gko mice demonstrated that mortality is associated with unchecked tachyzoite replication. Nevertheless, both wt and gko animals developed a peritoneal inflammatory response that in gko animals was greater due to a 5- to 10-fold increase in the number of granulocytes recruited to the site of infection. In addition, IL-12 production in gko mice was both unimpaired and functional since a significant, albeit lower than wt, IL-12-dependent NK cell response developed in these animals. Regardless, no evidence for an IFN-gamma-independent protective function for IL-12 or NK cells was apparent since in vivo treatment of gko mice with an IL-12-neutralizing mAb ablated the NK cell response, but did not decrease survival. Together, these data identify distinct functions for IL-12 and IFN-gamma in host resistance to T. gondii: IL-12 precedes and initiates synthesis of IFN-gamma, while the latter lymphokine directly controls parasite growth and diminishes the contribution of IL-4- and IL-5-producing T cell subsets.