Correlations of Toxoplasma gondii-specific immunoglobulin M (IgM) and IgG production, antigen-specific T-cell activation, and the number of brain cysts were compared in immunocompetent CBA/J (H-2k), C3H/He (H-2k), and B-cell-deficient CBA/N (H-2k) mice. Almost all of the C3H/He mice (94%) survived in comparison to CBA/J (71%) and CBA/N (53%) mice following infection with 20 cysts of Me 49, an avirulent strain of T. gondii. The mortality in susceptible mice was reduced by treatment of the animals with sulfadiazine during the acute stage of infection. Decreased mortality in CBA/J and C3H/He mice as well as in B-cell-deficient mice was paralleled by formation of fewer brain cysts. The Toxoplasma-specific T-cell proliferation was markedly enhanced in all three strains at day 15 postinfection but not at day 45 postinfection when compared to animals not treated with the drug. In contrast, Toxoplasma-specific IgM and IgG levels were lower in CBA/J and CBA/N mice treated with sulfadiazine than in untreated mice of these strains. Although CBA/N mice developed almost no humoral response either with or without drug treatment, they produced fewer brain cysts than normal CBA/J mice. The results indicate a major role of cell-mediated immunity in protection against an acute Toxoplasma infection.