Cross-protection between two serotypes of Group A streptococci was demonstrated. Type 55 strain 2004 and type 60 strain 365 shared a cross-protective relationship in one direction: type 55 antiserum possessed opsonophagocytic activity against type 60, but type 60 antiserum was inactive against type 55. Agar-gel diffusion tests with both types, their antisera, and reciprocally absorbed sera showed that type 55 possesses two M antigens; one of them is identical to that of type 60 and is responsible for the cross-protection. This cross-protection was found in sera of patients during an outbreak of acute glomerulonephritis caused by type 55. Fifty percent of the patients who developed immunity against the infecting type 55 also developed immunity against type 60 as tested by opsonophagocytic or bactericidal tests. None of the sera tested possessed a significant amount of opsonophagocytic activity against control types of group A streptococci.