The role of interleukin 10 (IL-10) and gamma interferon (IFN-gamma) on the development of pathology in human Chagas' disease was investigated. Two categories of patients, low and high producers of IFN-gamma, were identified based on the levels of secretion of this cytokine in the supernatant of peripheral blood mononuclear cell (PBMC) cultures. Eighty-three percent of the patients presenting with cardiac disease (CARD) of different degrees and 59% of the patients with the indeterminate form of disease (IND) were identified as high IFN-gamma producers. PBMC from IND patients classified as low IFN-gamma producers secreted significantly higher amounts of IL-10 than did those from other groups. Flow cytometry analysis demonstrated that in PBMC from the IND group, the majority of the IL-10-producing cells were monocytes (CD14(High+) cells), whereas in the CARD group, the major sources of IFN-gamma were T lymphocytes (CD3(+) CD4(+) cells). These results suggest an association between the production of IFN-gamma by CD3(+) CD4(+) cells and morbidity in Chagas' disease, whereas the production of IL-10 by macrophages/monocytes leads to regulation of the immune response in IND patients. We hypothesize that an exacerbated production of IFN-gamma against Trypanosoma cruzi antigens favors the development of a strong Th1 response in CARD patients, which leads to progression of heart disease.