Twenty-one adult volunteers were immunized at monthly intervals with three doses of purified type 1 M protein of group A Streptococcus. The soluble vaccine in buffer was administered by aerosol spray into the nares and oropharynx; 23 control subjects received a buffer placebo in the same manner. Antibody responses were observed in sera and nasal washings of some but not all vaccinees. Approximately 30 days after the last dose, all subjects were challenged with homologous streptococci applied by swab to the pharyngeal-tonsillar areas. In a double-blind system of evaluation, physical signs and symptoms were followed for assessment of infection. Illness was defined on the basis of a positive throat culture, fever, a twofold increase in white blood cell count over baseline, exudative pharyngitis, and cervical adenopathy. By these criteria four vaccinees and II controls were obviously ill. One vaccinee and six controls were questionably ill, fulfilling some but not all of the criteria. Sixteen vaccinees and six controls were not ill (P < 0.001). Positive throat cultures were observed in five vaccinees and 19 controls (P < 0.001). Penicillin was administered five days after challenge. No poststreptococcal sequelae or other complications were observed. Thus local immunization with M protein apparently can prevent both colonization and clinical illness after challenge with homologous streptococci.