Although immune responses against group A streptococci and the heart have been correlated with antibodies and T cell responses against cardiac myosin, there is no unifying hypothesis about carditis caused globally by many different serotypes. Our study identified disease-specific epitopes of human cardiac myosin in the development of rheumatic carditis in humans. We found that immune responses to cardiac myosin were similar in rheumatic carditis among a small sample of worldwide populations, in which immunoglobulin G targeted human cardiac myosin epitopes in the S2 subfragment hinge region within S2 peptides containing amino acid residues 842-992 and 1164-1272. An analysis of rheumatic carditis in a Pacific Islander family confirmed the presence of potential rheumatogenic epitopes in the S2 region of human cardiac myosin. Our report suggests that cardiac myosin epitopes in rheumatic carditis target the S2 region of cardiac myosin and are similar among populations with rheumatic carditis worldwide, regardless of the infecting group A streptococcal M serotype.