Trypanosoma cruzi kinetoplastid membrane protein-11 (KMP-11) is able to induce protective immunity in mice. In humans, T-cell immunity during Chagas disease has been documented using parasite antigens allowing the identification of specific CD8(+) T cells. However, little is known about the CD4(+) T-cell response during the evolution of the disease. In this paper, the induction of a natural CD4(+) T-cell response against the KMP-11 protein in T. cruzi infected humans was studied to assess whether this parasite-derived protein could be processed, presented and detected as a major histocompatibility complex class II restricted epitope. The results show that helper T cells from 5 out of 13 chagasic patients specifically produced interferon-gamma after exposure to the KMP-11 antigen, whereas healthy donors and non-chagasic cardiopathic patients did not respond. This is the first description of T. cruzi KMP-11 protein recognition by CD4(+) T cells in chronic chagasic patients.