Although gamma interferon (IFN-γ) and interleukin-10 (IL-10) have been shown to be critically involved in the pathogenesis of African trypanosomiasis, the contributions to this disease of CD4(+) and CD8(+) T cells, the major potential producers of the two cytokines, are incompletely understood. Here we show that, in contrast to previous findings, IFN-γ was produced by CD4(+), but not CD8(+), T cells in mice infected with Trypanosoma brucei. Without any impairment in the secretion of IFN-γ, infected CD8(-/-) mice survived significantly longer than infected wild-type mice, suggesting that CD8(+) T cells mediated mortality in an IFN-γ-independent manner. The increased survival of infected CD8(-/-) mice was significantly reduced in the absence of IL-10 signaling. Interestingly, IL-10 was also secreted mainly by CD4(+) T cells. Strikingly, depletion of CD4(+) T cells abrogated the prolonged survival of infected CD8(-/-) mice, demonstrating that CD4(+) T cells mediated protection. Infected wild-type mice and CD8(-/-) mice depleted of CD4(+) T cells had equal survival times, suggesting that the protection mediated by CD4(+) T cells was counteracted by the detrimental effects of CD8(+) T cells in infected wild-type mice. Interestingly, CD4(+) T cells also mediated the mortality of infected mice in the absence of IL-10 signaling, probably via excessive secretion of IFN-γ. Finally, CD4(+), but not CD8(+), T cells were critically involved in the synthesis of IgG antibodies during T. brucei infections. Collectively, these results highlight distinct roles of CD4(+) and CD8(+) T cells in the context of IFN-γ and IL-10 during T. brucei infections.