Selection pressures exerted on Staphylococcus aureus by host factors during infection may lead to the emergence of regulatory phenotypes better adapted to the infection site. traits convenient for persistence may be fixed by mutation thus turning these mutants into microevolution endpoints. The feasibility that stable, non-encapsulated S. aureus mutants can regain expression of key virulence factors for survival in the bloodstream was investigated. S. aureus agr mutant HU-14 (IS256 insertion in agrC) from a patient with chronic osteomyelitis was passed through the bloodstream using a bacteriemia mouse model and derivative P3.1 was obtained. Although IS256 remained inserted in agrC, P3.1 regained production of capsular polysaccharide type 5 (CP5) and staphyloxanthin. Furthermore, P3.1 expressed higher levels of asp23/SigB when compared with parental strain HU-14. Strain P3.1 displayed decreased osteoclastogenesis capacity, thus indicating decreased adaptability to bone compared with strain HU-14 and exhibited a trend to be more virulent than parental strain HU-14. Strain P3.1 exhibited the loss of one IS256 copy, which was originally located in the HU-14 noncoding region between dnaG (DNA primase) and rpoD (sigA). this loss may be associated with the observed phenotype change but the mechanism remains unknown. in conclusion, S. aureus organisms that escape the infected bone may recover the expression of key virulence factors through a rapid microevolution pathway involving SigB regulation of key virulence factors. Staphylococcus aureus is a transient, sometimes permanent member of the human microbiota in the nares and skin of a significant number of healthy individuals. As predisposing conditions emerge in the host, this opportunistic species may cause infections with different severity, ranging from mild skin and soft tissue infection to severe disseminated disease 1,2. Treatment of S. aureus infections is hampered by widespread dissemination of methicillin-resistant S. aureus (MRSA) 3 and by the frequent emergence of S. aureus with low level resistance to vancomycin 4. Whereas MRSA was primarily considered a nosocomial pathogen 5 , it is now unanimously accepted that MRSA also affects individuals of the general community with no previous exposure to health care settings 6,7. Up to 1.5-2% of patients receiving an orthopedic prosthetic device becomes infected and a significant number of these infections are caused by S. aureus. Most osteomyelitis caused by S. aureus become refractory to antibiotic treatment soon after bacteria settles on the prosthetic device surface and in bone tissue 1 .