Immunization with cardiac myosin induces T cell-mediated myocarditis in genetically predisposed mice and serves as a model for autoimmune heart disease. This study was undertaken to identify pathogenic epitopes on the myosin molecule. Our approach was based on the comparison of the pathogenicity between cardiac ( ␣ -) myosin and soleus muscle ( ␤ -) myosin. We show that ␣ -myosin is the immunodominant isoform and induces myocarditis at high severity and prevalence whereas ␤ -myosin induces little disease. Therefore the immunodominant epitopes of ␣ -myosin must reside in regions of different amino acid sequence between ␣ -and ␤ -myosin isoforms. Cardiac myosin peptides corresponding to these regions of difference were synthesized and tested for their ability to induce inflammatory heart disease. Three pathogenic peptides were identified. One peptide that is located in the head portion of the molecule induced severe myocarditis, whereas two others that reside in the rod portion possessed only minor pathogenicity. The identification of pathogenic epitopes on the cardiac myosin molecule will allow detailed studies on the recognition of this antigen by the immune system and might be used to downmodulate ongoing heart disease. (