Several microbial pathogens have been reported to interact with glycosaminoglycans (GAGs) on cell surfaces and in the extracellularmatrix. Herewe demonstrate thatM protein, a major surface-expressed virulence factor of the human bac-terial pathogen, Streptococcus pyogenes, mediates binding to various forms of GAGs. Hence, S. pyogenesstrains expressing a large number of different types of M proteins bound to dermatan sulfate (DS), highly sulfated fractions of heparan sulfate (HS) and heparin, whereas strains deficient in M protein surface expression failed to interact with these GAGs. .