Some isolates of the significant human pathogen Streptococcus pyogenes, including virulent strains of the M1 serotype, secrete protein SIC. This molecule, secreted in large quantities, interferes with complement function. As a result of natural selection, SIC shows a high degree of variation. Here we provide a plausible explanation for this variation and the fact that strains of the M1 serotype are the most frequent cause of severe invasive S. pyogenes infections. Thus, protein SIC was found to inactivate human neutrophil alpha-defensin and LL-37, two major antibacterial peptides involved in bacterial clearance. This inactivation protected S. pyogenes against the antibacterial effect of the peptides. Moreover, SIC isolated from S. pyogenes of the M1 serotype was more powerful in this respect than SIC variants from strains of M serotypes 12 and 55, serotypes rarely connected with invasive infections.