We compared the relative resistance and soluble variant surface glycoprotein (VSG)-specific responses in (C57BL/6 x BALB/c)-F1 (B6B-F1) and C3H mice during infection with Trypanosoma brucei brucei, the hemoprotozoan parasite causing a debilitating disease in man and livestock. We demonstrated that C3H mice are relatively more trypanosusceptible, as evidenced by their reduced ability to control parasitemia and shorter survival time, than B6B-F1 mice. Quantitative differences in the pattern of cytokine and antibody (Ab) production were observed between the 2 mouse strains following infection with T. b. brucei. Thus, although both mouse strains recorded detectable levels of IFN-gamma, TNF-alpha, NO and IL-10 in plasma and lymph nodes, as well as plasma IgM, IgG1, IgG2a, IgG2b and IgG3 Abs against VSG, the susceptible C3H mice only exhibited trace levels of Abs of all isotypes and yet produced elevated levels of IFN-gamma, TNF-alpha and NO, compared to the relatively trypanotolerant B6B-F1 mice. In aggregate, these data strongly suggest that trypanosome-infected C3H mice have an immunological defect, manifested not only by suppression at the B cell clonal level, but also at the level of protective T cell and macrophage phenotypes.