In this study, we demonstrate that Kupffer cells in the livers of highly susceptible BALB/c mice infected with Trypanosoma congolense were loaded with trypanosomal antigen and appeared highly activated. This was associated with an enlarged capillary bed in the livers and decreased blood pressure of these mice towards the terminal stage. Blocking of murine IL‐10 receptor (IL‐10R)in vivo shortened the survival time of highly susceptible T. congolense‐infected BALB/c mice. Anti‐IL‐10R treatment decreased the survival of relatively resistant T. congolense‐infected C57BL/6 mice dramatically. Blocking of the IL‐10R also significantly shortened the survival time of mice infected with T. brucei. The acute death of trypanosome‐infected mice treated with anti‐IL‐10R antibodies in vivo was associated with focal liver necrosis, with significantly increased plasma levels of IL‐6, IL‐10, IL‐12p40 and IFN‐γ and enhanced synthesis of IL‐6, IL‐12p40 and IFN‐γ by spleen cell cultures. Anti‐IL‐10R‐induced death of T. congolense‐infected C57BL/6 mice could be prevented by administration of a neutralizing antibody specific forIFN‐γ. We conclude that phagocytosis of a critical number of trypanosomes by Kupffer cells leads to a systemic inflammatory response syndrome and, depending on the degree of Kupffer cell activation, is followed by death that is mediated by IFN‐γ. The role of trypanosome‐pulsed macrophages, T cells and genetic influences is discussed in a synopsis.