Twenty-one healthy siblings of patients with rheumatic fever were vaccinated with a type 3 streptococcal M protein. During and following vaccination these children experienced 18 group-A streptococcal infections (none type 3) with a rise in antistreptolysin O titer. Two infections were followed by definite rheumatic fever and one by probable rheumatic fever. This high rate contrasts with the observation of five cases of rheumatic fever in 447 similar streptococcal infections in nonvaccinated siblings. This experience necessitates giving consideration to the possibility that streptococcal vaccination of children may alter their tissue response to subsequent streptococcal infection. Most importantly, this experience indicates the need for extreme caution in the use of streptococcal Vaccines in human subjects.