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This paper investigates the role of specific immune factors on the course of infection in genetic knockout (gko) mice infected with 3 different strains of Neospora caninum. Survival time and parasite persistence were examined in interferon-g (IFN- g), tumor necrosis factor receptor-2 (TNFR2), interleukin 10 (IL-10), beta 2 microglobulin ( b2M), and inducible nitric oxide synthase (iNOS2) gko or wild-type (wt) mice following infection with either pathogenic (NC-1 or NC-2) or attenuated (NCts-8) N. caninum strains. Infection with NC-1 was 100% lethal in IFN-g gko mice, as evidenced by mean survival times of 10-13 days, depending on the challenge dose used. TNFR2 and b2M gko mice infected with NC-1 or NC-2 strain demonstrated partial susceptibility to disease, as evidenced by histopathology and survival curves. TNFR2 or b2M gko mice were not susceptible to infection with NCts-8, on the basis of absence of pathology and lack of mortality. Lack of mortality and minimal histopathology scores demonstrated that NC-1, NC-2, and NCts-8 infections were avirulent in IL-10 and iNOS2 gko mice. Adoptive transfer of immune cells from NCts-8 vaccinated normal syngeneic mice into IFN-g gko mice significantly (P , 0.05) prolonged mean survival times at all 3 challenge doses of NC-1 but failed to protect against mortality. Interestingly, there was a notable change in the tissue tropism of tachyzoites from the lung and brain in immunocompetent wt, TNFR2 gko, IL-10 gko, b2M gko, and iNOS2 gko mice to the liver and spleen in IFN-g gko mice when challenged with N. caninum. On the basis of these results in gko mice, IFN-g is a critical cytokine in the host response against acute neosporosis. Neospora caninumis an apicomplexan parasite that causes a variety of symptoms in several mammalian species. The largest economic cost caused by this parasite is because of abortions in dairy and beef cows. If abortions do not occur, infected off- spring can be born weak or lame or both. Asymptomatic, se- ropositive, replacement calves can lead to maintenance of N. caninum infection in these dairy and beef herds. Because of the close taxonomic relationship between Toxo- plasma gondii and N. caninum, it can be postulated that the same immune cells and soluble mediators important for protec- tion in T. gondii infections (Lee et al., 1999) may play a similar role in host protection against N. caninum. For example, T. gondii infections in interferon