Methicillin-resistantStaphylococcus aureusis problematic both in hospitals and in the community. Currently, we have limited understanding of mechanisms of innate immune evasion used byS. aureusTo that end, we created an isogenic deletion mutant in strain MW2 (USA400) of thesaeR/S2-component gene regulatory system and studied its role in mouse models of pathogenesis and during human neutrophil interaction. In this study, we demonstrate thatsaeR/Splays a distinct role inS. aureuspathogenesis and is vital for virulence of MW2 in a mouse model of sepsis. Moreover, deletion ofsaeR/Ssignificantly impaired survival of MW2 in human blood and after neutrophil phagocytosis. Microarray analysis revealed that SaeR/S of MW2 influences expression of a wide variety of genes with diverse biological functions. These data provide new insight into how virulence is regulated inS. aureusand associates a specific staphylococcal gene-regulatory system with invasive staphylococcal disease.