Immunity after GAS infection is traditionally seen as relying on emm-type specific antibody response. However, the evidences supporting this paradigm are in fact relatively limited. We have analyzed the M protein immune response after GAS skin infection in Fiji. We investigated the human serological response to GAS impetigo in Fijian schoolchildren, focusing on 3 major emm clusters (E4, E6, and D4). Pre- and post infection sera were assayed by ELISA assay with N-terminal M peptides and bactericidal assays using the infecting-type strain, emm cluster–related strains, and nonrelated strains. While the responses were highly variable, numerous instances of cross-reactive killing were observed. Our study confirms the existence of emm-type specific immunity, but suggests that this is an incomplete picture and that a combination of “cluster-specific” and “type-specific” responses occur. Our study suggests that cross-reactive immune responses occur following skin infection and raises hope for the development of a broadly protective multivalent vaccine.