BALB/c mice are highly susceptible to Trypanosoma congolense infection, whereas C57BL/6 mice are relatively resistant. Overproduction of interferon-gamma (IFN-gamma) and other proinflammatory cytokines contribute to death in susceptible mice. Here, we show that lymphotoxin beta-deficient (LTbeta(-/-)) mice are more resistant than wild-type (WT) mice to T. congolense infection, as shown by a lower parasitemia level and a longer survival duration. The enhanced resistance of LTbeta(-/-) mice was associated with undetectable or low serum levels of proinflammatory cytokines (i.e., tumor necrosis factor-alpha, interleukin [IL]-6, IL-12, and monocyte chemotactic protein-1). Although infected LTbeta(-/-) mice had high numbers of CD4(+)CD25(+)Foxp3(+) cells and high serum IL-10 levels, these cells were not the major producers of IL-10. Treatment of LTbeta(-/-) mice with anti-IL-10R monoclonal antibody abolished their enhanced resistance, whereas depletion of CD25(+) cells further enhanced resistance among infected WT and LTbeta(-/-) mice. These results suggest that LTbeta plays critical role in regulating the outcome of T. congolense infection in mice.