Summary: Group A streptococcal M proteins of serotypes 3 and 12 cross-react as a result of shared antigenic determinants. These cross-reactions are seen in passive hemagglutination assays and in lines of identity in immunodiffusion plates with antisera from rabbits immunized with purified M protein vaccines. Rabbits immunized with one of types 3 or 12 M protein vaccines produce antibodies that are bactericidal only for the homologous serotype. Children with upper respiratory infections caused by either types 3 or 12 group A streptococci develop antibodies to both serotypes. The implications of these findings are discussed with respect to streptococcal immunization of humans with M protein vaccines.