Four prophages (φNM1–4) were identified in the genome of Staphylococcus aureus Newman, a human clinical isolate. φNM1, φNM2 and φNM4, members of the siphoviridae family, insert at different sites (poiA, downstream of isdB and geh) in the staphylococcal chromosome. φNM3, a β-haemolysin (hlb) converting phage, encodes modulators of innate immune responses (sea, sak, chp and scn) in addition to other virulence genes. Replication of φNM1, φNM2 and φNM4 occurs in culture and during animal infection, whereas φNM3 prophage replication was not observed. Prophages were excised from the chromosome and S. aureus variants lacking φNM3 or φNM1, φNM2 and φNM4 displayed organ specific virulence defects in a murine model of abscess formation. S. aureus Newman lacking all four prophages was unable to cause disease, thereby revealing essential contributions of prophages to the pathogenesis of staphylococcal infections.