BACKGROUND: HIV-positive patients at HELP/PSI, Inc, an in-patient drug rehabilitation center, had a high baseline prevalence of Staphylococcus aureus colonization (49%) and incidence of infection (17%) in a previous year-long study.METHODS: A randomized, double-blinded, placebo-controlled study was conducted to determine whether repeated nasal application of mupirocin ointment would decrease the odds of S. aureus nasal colonization in 100 HELP/PSI patients over an 8-month period. A 5-day course of study drug was given monthly, and colonization was assessed at baseline and 1 month after each treatment. S. aureus infection was a secondary outcome.RESULTS: In repeated-measures analysis, mupirocin reduced the odds of monthly S. aureus nasal colonization by 83% compared with placebo [adjusted odds ratio (ORadj) = 0.17; P < 0.0001]. Subjects colonized at study entry had a 91% reduction in subsequent colonization (ORadj = 0.09; P < 0.0001). Mupirocin also suppressed S. aureus colonization in subjects not colonized at baseline (ORadj = 0.23; P = 0.006). There was no difference in infection rates between the mupirocin and placebo groups (hazard ratio = 0.49, P = 0.29).CONCLUSIONS: Monthly application of nasal mupirocin significantly decreased S. aureus colonization in HIV patients in residential drug rehabilitation. Monthly mupirocin application has a potential role in long-term care settings or in HIV-positive patients with high rates of S. aureus colonization and infection.