Group A streptococci (GAS) are highly prevalent human pathogens whose primary ecological niche is the superficial epithelial layers of the throat and/or skin. Many GAS strains having a strong tendency to cause pharyngitis are distinct from strains that tend to cause impetigo; thus, genetic differences between them may confer host tissue-specific virulence. In this study, the FbaA surface protein gene is found to be present in most skin specialist strains, but largely absent from a genetically-related subset of pharyngitis isolates. Using an ΔfbaA mutant constructed in the impetigo strain Alab49, loss of FbaA resulted in a slight but significant decrease in GAS fitness in a humanized mouse model for impetigo; the ΔfbaA mutant also exhibited decreased survival in whole human blood due to phagocytosis. Using assays with highly sensitive outcome measures, Alab49ΔfbaA was compared to other isogenic mutants lacking M- or FCT-region virulence genes known to be disproportionately associated with classical skin strains. FbaA and PAM (i.e., M53 protein) have additive effects in promoting GAS survival in whole blood. In addition to FbaA and PAM, other Mga-regulated genes make a significant contribution to virulence in both the impetigo and phagocytosis assays. The pilus adhesin tip protein Cpa promotes Alab49 survival in whole blood, and appears to fully account for the antiphagocytic effect attributable to pili. That numerous skin strain-associated virulence factors make slight but significant contributions to virulence underscores the incremental contributions to fitness of individual surface protein genes and the multifactorial nature of GAS-host interactions.