A biological role for the non-immune binding of human IgG by group A streptococci is evidenced by its strong association with a subpopulation of strains giving rise to tissue-specific infection. IgG-binding activity lies within many of the M and M-like surface proteins (encoded by emm genes), and several structurally distinct IgG-binding sites are known to exist. In this report, two adjacent IgG-binding domains, differing in their specificity for human IgG subclasses, are localized within the M-like protein, protein H. The putative coding regions for the two IgG-binding domains were mapped for 82 epidemiologically unrelated strains. Both coding regions are associated with phylogenetically distant emm genes, supporting a role for horizontal transfer and intergenomic recombination in the evolution of emm genes. In most instances, the two coding regions are tightly linked, suggesting that there exist strong selective pressures to maintain a two-domain binding motif. Both coding regions are found among all strains bearing emm gene markers associated with impetigo lesions as the principal tissue reservoir, but are absent from most strains that exhibit markers for a predominant nasopharyngeal reservoir. The data support the hypothesis that the pathogenic potential of an isolate is dictated, at least in part, by its unique array of multifunctional emm gene products.