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Staphylococcus aureus (S. aureus) is an independent risk factor for orthopaedic surgical site infection (SSI). To determine whether a preoperative decolonization protocol reduces S. aureus SSIs, we conducted a prospective observational study of patients undergoing elective total joint arthroplasty (TJA) at our institution, with two control groups. The concurrent control group comprised patients of surgeons who did not participate in the intervention study. The preintervention control group comprised patients of participating surgeons who had undergone elective TJA during the year before the study. Patients in the intervention group were screened preoperatively for S. aureus by nasal swab cultures. S. aureus carriers were decolonized with mupirocin ointment to the nares twice daily and chlorhexidine bath once daily for 5 days before surgery. All 164 of 636 participants (26%) who tested positive completed the decolonization protocol without adverse events and had no postoperative S. aureus SSIs at 1-year followup. In contrast, 1330 concurrent control patients had 12 S. aureus infections. If these infections had occurred in the 26% of patients expected to be nasal carriers of S. aureus at a given time, the infection rate would have been 3.5% (12 of 345) in the control group. In addition, the overall infection rate of the participating surgeons, including nonstaphylococcal infections, decreased from 2.6% during the preintervention period to 1.5% during the intervention period, translating to an adjusted economic gain of $231,741 for the hospital. The data suggest a preoperative decolonization protocol reduces S. aureus SSIs in patients undergoing TJA. Level of Evidence: Level II, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

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