Two serologically distinct antibodies directed against different antigenic sites on the Group A carbohydrate were detected in human sera by agglutination techniques. Agglutinins with A-variant specificity were demonstrable by the direct agglutination of purified A-variant cell walls, whereas indirect Coombs-type agglutinins with Group A specificity were demonstrable with Group A cell walls. Selective adsorption with homologous cell walls as well as inhibition studies with the soluble carbohydrates confirmed the specificity of the two types of agglutinins. There was an obvious correlation between the magnitude of the antistreptolysin O titer, and the direct Group A-variant and the indirect Group titers. These data suggest that indirect anti-Group A agglutinins and direct anti-Group A-variant agglutinins are produced following a Group A streptococcal infection.