Staphylococcus aureusis an opportunistic pathogen and chief among bloodstream-infecting bacteria.S. aureusproduces an array of human-specific virulence factors that may contribute to immune suppression. Here, we defined the response of primary human phagocytes following infection withS. aureususing RNA-sequencing (RNA-Seq). We found that the overall transcriptional response toS. aureuswas weak both in the number of genes and in the magnitude of response. Using an ex vivo bacteremia model with fresh human blood, we uncovered that infection withS. aureusresulted in the down-regulation of genes related to innate immune response and cytokine and chemokine signaling. This muted transcriptional response was conserved across diverseS. aureusclones but absent in blood exposed to heat-killedS. aureusor blood infected with the less virulent staphylococcal speciesStaphylococcus epidermidis. Notably, this signature was also present in patients withS. aureusbacteremia. We identified the master regulatorS. aureusexoprotein expression (SaeRS) and the SaeRS-regulated pore-forming toxins as key mediators of the transcriptional suppression. TheS. aureus–mediated suppression of chemokine and cytokine transcription was reflected by circulating protein levels in the plasma. Wild-typeS. aureuselicited a soluble milieu that was restrictive in the recruitment of human neutrophils compared with strains lackingsaeRS. Thus,S. aureusblunts the inflammatory response resulting in impaired neutrophil recruitment, which could promote the survival of the pathogen during invasive infection.