Bacterial invasion of host tissues triggers polymorphonuclear leukocytes to release DNA [neutrophil extracellular traps (NETs)], thereby immobilizing microbes for subsequent clearance by innate defenses including macrophage phagocytosis. We report here that Staphylococcus aureus escapes these defenses by converting NETs to deoxyadenosine, which triggers the caspase-3-mediated death of immune cells. Conversion of NETs to deoxyadenosine requires two enzymes, nuclease and adenosine synthase, that are secreted by S. aureus and are necessary for the exclusion of macrophages from staphylococcal abscesses. Thus, the pathogenesis of S. aureus infections has evolved to anticipate host defenses and to repurpose them for the destruction of the immune system.