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Background: Surgical site infections continue to be one of the leading causes of nosocomial infections leading to increased patient morbidity and mortality, length of hospital stays and healthcare expenditure. Amongst the many pathogens, Staphylococcus aureus is a leading cause and many efforts have and continue to be made to reduce their incidence. One such intervention is the use of intranasal mupirocin in the preoperative setting to reduce nasal carriage of S. aureus. Recent studies suggest there seems to be a benefit to using mupirocin in this manner to reduce surgical site infections in cardiac and orthopedic surgical populations. This systematic review will address the question of whether such an intervention will reduce surgical site infections in non-cardiac and non-orthopedic surgical populations. Methods: I searched MEDLINE and Embase databases until 05/2015 in order to identify prospective randomized controlled trials addressing the use of mupirocin in reducing surgical site infections which yielded 162 search results. The studies were selected based on pre-specified criteria. Included studies were prospective randomized controlled trials comparing intranasal mupirocin or intranasal mupirocin and topical chlorhexidine to either standard treatment or placebo. The primary outcome I was interested in was the incidence of surgical site infections. Other outcomes included incidence of Staphylococcus aureus specific surgical site infections, narrative or numerical reports on harms, patient compliance, resistance to mupirocin, and mortality rates. I only chose studies that followed patients for a minimum of 30 days postoperatively. I performed duplicate exclusions, title, and abstract and full text review in order to include 4 studies out of the 162 initial search results. Subsequently, I critically appraised each included study in order to perform a risk of bias assessment. I then abstracted study characteristics, patient characteristics, and outcomes using a standardized data abstraction table. Lastly, I synthesized the abstracted data as part of my qualitative analysis. Results: There were no reports of statistically significant reductions in either overall surgical site infections or S. aureus specific surgical site infections in the four studies included in this systematic review. Reports of resistance to mupirocin were only included in one study. Data on adverse reactions were reported in three of the four included studies and mostly consisted of narrative reports stating that the treatment regimen was well tolerated. Numerical data on incidence of adverse reactions provided in one study were similar in both the treatment and control arms. No life threatening adverse reactions were reported in the included studies. Only one of the four studies provided numerical data on patient compliance whereas the other included studies only provided cursory information on compliance. Conclusions: Given that there were no statistically significant reductions in surgical site infections or S. aureus specific surgical site infections in the included studies that used mupirocin alone or a combination of both mupirocin and chlorhexidine compared to placebo or standard treatment I do not have sufficient evidence to recommend preoperative prophylaxis in non-cardiac and non-orthopedic surgical populations. However, given that the included studies have limited internal and/or external validity and because the same intervention has been shown to be potentially beneficial in cardiac and orthopedic surgical populations I also don't have evidence to recommend against it. No conclusions can be drawn regarding resistance or patient compliance as only one study reported on these outcomes. Given the limited number of studies addressing this question in non-orthopedic and non-surgical patients there needs to be additional randomized controlled trials that are sufficiently powered in these patient populations before definitive conclusions can be drawn.