Of all nosocomial infections, those caused by Staphylococcus aureus should be among the most preventable because the patient is usually colonized with the causative strain well before onset of actual infection and before entering the hospital (1). These facts suggest the following strategy: eliminate the colonizing strain, and subsequent infection should not occur. In several studies, mupirocin topically applied to the anterior nares, a common site for S. aureus colonization, has been highly effective in eradicating S. aureus carriage for as long as several weeks (2–3). Because hospitalization constitutes a defined period of increased risk, mupirocin could be an ideal prophylactic agent against nosocomial S. aureus infection. This logic notwithstanding, 2 relatively large, well-designed, randomized, placebo-controlled trials (4–5), the most recent of which is reported by Wertheim and colleagues in this issue (5), have failed to demonstrate that mupirocin prophylaxis reduces nosocomial S. aureus infections. A third large study found no decrease in the rate of S. aureus surgical site infections, the primary end point of the trial, although nasal carriers had fewer S. aureus nosocomial infections when the end point was infection at any site (6).