The effectiveness and safety of mupirocin calcium ointment applied to the anterior part of the nares for 5 days in the eradication of nasal carriage of Staphylococcus aureus was investigated in a placebo-controlled, double-blind study. Subjects were healthy medical center staff who had two positive cultures of the anterior nares for S aureus. Antimicrobial susceptibility, phage typing, and restriction endonuclease analysis of plasmid DNA were used to monitor the identity of relapsing and persisting strains. Mupirocin eliminated 74% of S aureus at early follow-up and 91% of original strains. At 4 weeks, 78% of the original strains were eradicated, whereas all of the placebo group remained colonized. Recolonization with mupirocin-resistant strains occurred in six patients, but these were of different phage and plasmid types from the original isolates. None of the subjects had serious adverse effects. Applied intranasally for 5 days, a calcium preparation of mupirocin in a paraffin base is effective in eliminating S aureus nasal carriage and is well tolerated.