Previous studies have associated the production of IL-10 with suppression of the protective cell-mediated immune response to Trypanosoma cruzi. To further understand the role of IL-10 in the resistance to and pathogenesis of Chagas' disease, we infected C57BL/6 wild-type (IL-10 +/+) or C57BL/6 IL-10 knockout (IL-10 -/-) mice with the virulent Tulahuen strain of T. cruzi. IL-10 -/- mice had a lower parasite burden and higher levels of serum TNF-alpha, IL-12, and IFN-gamma compared with infected IL-10 +/+ mice. However, infection resulted in earlier mortality of IL-10 -/- mice compared with IL-10 +/+ controls. The earlier mortality of IL-10 -/- mice could be reversed by administering rIL-10 or a neutralizing Ab specific for IL-12. A role for T cells in the early mortality of IL-10 -/- mice was suggested by experiments in which SCID IL-10 -/- mice infected with T. cruzi had a delay in time to death and significantly lower serum levels of IFN-gamma compared with IL-10 -/- mice. Furthermore, treatment of infected IL-10 -/- mice with a mAb specific for CD4 resulted in reduced serum levels of IFN-gamma and a delay in time to death. Altogether, our results demonstrate for the first time that during infection with T. cruzi there is a critical requirement for IL-10 to prevent the development of a pathologic immune response associated with CD4+ T cells and overproduction of IL-12.