Using interleukin-10 (IL-10)-deficient (IL-10(-/-)) mice, previous studies revealed a pathological immune response after infection with Trypanosoma cruzi that is associated with CD4(+) T cells and overproduction of proinflammatory cytokines. In this study we further investigate the pathology and potential mediators for the mortality in infected animals. T. cruzi-infected IL-10(-/-) mice showed reduced parasitemia accompanied by increased systemic release of gamma interferon (IFN-gamma), IL-12, and reactive nitrogen intermediates and overproduction of tumor necrosis factor alpha (TNF-alpha). Despite this early resistance, IL-10(-/-) mice died within the third week of infection, whereas all control mice survived acute infection. The clinical manifestation with weight loss, hypothermia, hypoglycemia, hyperkalemia, and increased liver-derived enzymes in the blood together with hepatic necrosis and intravascular coagulation in moribund mice indicated a toxic shock-like syndrome, possibly mediated by the systemic TNF-alpha overproduction. Indeed, high production of systemic TNF-alpha significantly correlated with mortality, and moribund mice died with critically high TNF-alpha concentrations in the blood. Consequent treatment with anti-TNF-alpha antiserum attenuated pathological changes in T. cruzi-infected IL-10(-/-) mice and significantly prolonged survival; the mice died during the fourth week postinfection, again with a striking correlation between regaining high systemic TNF-alpha concentrations and the time of death. Since elevated serum IL-12 and IFN-gamma concentrations were not affected by the administration of antiserum, these studies suggest that TNF-alpha is the direct mediator of this toxic shock syndrome. In conclusion, induction of endogenous IL-10 during experimentally induced Chagas' disease seems to be crucial for counterregulating an overshooting proinflammatory cytokine response resulting in TNF-alpha-mediated toxic shock.