Introduction Staphylococcus aureus (S. aureus) is the leading nosocomial (hospital acquired) pathogen in hospitals globally, resulting in substantial morbidity, mortality and additional costs. Breast cancer wound infection can delay and even cause the omission of necessary adjuvant oncological treatment. Nasal carriers of S. aureus are a well defined risk factor for subsequent infections with this organism. Decolonization of nasal and extra nasal sites preoperative can reduce the risk of surgical site infections (SSIs) with S. aureus. The aim of this study was to evaluate the effect of patients screened with S. aureus nasal carriage on the incidence of SSI in a breast cancer surgery population. Methods A prospective cohort study was performed between April 2009 and December 2016 including all patients undergoing a breast cancer surgery. Patients were screened for S. aureus nasal carriage and, when tested positive, were subsequently treated with mupirocin nasal ointment and chlorhexidine soap. The control group was a cohort of patients from April 2009 till July 2011, who were not screened and not received treatment. Results A total of 1543 patients were included in this study. The rate of S. aureus infection was 1.1% (12 of 1071) for patients who were screened for S. aureus nasal carriage as compared with 2.5 % (12 of 472) for patients who were not screened for S. aureus carriage (relative risk of infection, 0.48; 95% confidence interval [CI], 0.194 to 0.974; p=0.038). Conclusion The number of surgical site for patients infected with S. aureus who were also operated for breast cancer can be significantly reduced by screening and decolonizing nasal carriers of S. aureus on admission.