Immunization with purified M protein, a component of the group A streptococcal cell wall, induces the formation of circulating antibody and delayed cutaneous hypersensitivity (DCH). The specificity of these responses was evaluated in guinea pigs and man, using types 1, 3, 6 and 12 M protein. In a study of 10 human adults, delayed hypersensitivity and circulating antibody to more than one M protein was usually present. In several individuals, in vitro cellular reactivity to several M proteins was found in the absence of detectable DCH and antibody. Female Hartley guinea pigs sensitized with specific M proteins were reactive to homologous and, to a lesser extent, heterologous serotypes when DCH or spleen cell reactivity was determined. High titer homologous antisera reacted with heterologous M proteins measured by passive hemagglutination; only opsonic antibody was type-specific. Cellular responses to M proteins, assayed by spleen cell reactivity and inhibition of peritoneal exudate cell migration 6 months after sensitization when antibody was no longer detectable, were as great as when titers were high. Unimmunized controls, or those given Freund's adjuvant without M protein manifested negative skin tests, did not produce circulating antibody or respond with significant cellular proliferation when challenged with M proteins.