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‐γ 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.