Purified streptococcal M protein extracted by nonionic detergent was used in an RIA and a solid-phase radiocompetitive inhibition assay to determine the nature of the immune response in both human beings and hyperimmunized rabbits to this complex antiphagocytic antigen. Results indicate that a type-specific response to an M antigen with the development of opsonic antibodies is the result of antibodies directed against the majority of the antigenic determinants of the molecule. Cross-reactions between certain M types on the other hand, are represented by antibodies directed against only a small percentage of these antigenic determinants. Results also suggest that avidity may play a role in the action of opsonic antibodies. However, the data indicate that factors besides avidity (i.e. sites bound by the antibodies) also seem essential for opsonization.