Four prophages (phi NM1-4) were identified in the genome of Staphylococcus aureus Newman, a human clinical isolate. phi NM1, phi NM2 and phi NM4, members of the siphoviridae family, insert at different sites (poiA, downstream of isdB and geh) in the staphylococcal chromosome. phi NM3, a beta-haemolysin (hlb) converting phage, encodes modulators of innate immune responses (sea, sak, chp and scn) in addition to other virulence genes. Replication of phi NM1, phi NM2 and phi NM4 occurs in culture and during animal infection, whereas phi NM3 prophage replication was not observed. Prophages were excised from the chromosome and S. aureus variants lacking phi NM3 or phi NM1, phi NM2 and phi NM4 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.