Preimmunization with attenuated Corpus Christi stain Trypanosoma cruzi provides survival to C3H mice and enhances resistance of C57 mice to Brazil strain infection. C3H(He) and C57 B1/6 mice surviving acute infection of T. cruzi are shown to have heart specific autoantibodies through acute and chronic infection. ELISA assays were performed using nondenatured extract of hearts from normal syngeneic mice as target antigen reacted with sera from immunized and/or infected mice. Surviving C3H mice developed a specific anti-heart response as early as Day 21 of infection and this response continued at a high level to Day 300. The response in C57 mice, both immunized-infected and infected only, increased to Day 100 followed by a decline in intensity. The heart specificity of the response in mice was suggested by negligible reaction of sera with smooth muscle preparations and a reduced autoreactivity with skeletal muscle. Laminin, a suggested target of autoimmunity in Chagas' disease, was shown not to be the target of the responses in these mice. Immunoaffinity-purified heart specific antibodies show strong cross-reactivity with parasite antigen and like purified parasite specific antibodies, reacted with heart antigen.