By means of the immunofluorescent staining technique, antisera to a wide variety of serological types of Group A and A variant streptococci were found to contain an antibody which reacted with mammalian striated muscle, both skeletal and cardiac, as well as with smooth muscle in the endocardium and in the media of arterioles. Similar heart-reactive antibodies were not present in antisera to most other groups of hemolytic streptococci and to other Gram-positive cocci. Chemical and serological studies clearly pointed to the cell (protoplast) membrane of the Group A streptococcus as the locus of the antigenic determinant of this heart-reactive antibody. In addition, preliminary studies suggested that the reaction between this streptococcal antibody and cardiac tissue represented an immunological relationship between the sarcolemma, the membrane of a mammalian muscle cell and the cell membrane of a bacterium, the hemolytic streptococcus.