BACKGROUND: In treating orthopedic infections, the long-term impact of vancomycin therapy on colonization by methicillin-resistant Staphylococcus aureus (MRSA) and the emergence of vancomycin-intermediate S. aureus is unknown. DESIGN: Prospective surveillance of the effect of long-term vancomycin therapy on colonization by MRSA and the emergence of vancomycin-intermediate S. aureus. METHODS: Thirty-four patients with MRSA osteomyelitis that was microbiologically documented were longitudinally observed for the emergence of vancomycin-intermediate S. aureus at 3 body sites (wound, anterior nares, and groin) during the initial period of vancomycin therapy and at the 2-month follow-up. Twenty patients received the standard dose (20 mg/kg/d) for 34 +/- 6 days and 14 patients received a high dose (40 mg/kg/d) of vancomycin for 37 +/- 9 days. RESULTS: During vancomycin treatment, global MRSA carriage (all body sites) fell from 100% to 25% in the group of patients receiving the standard dose of vancomycin, and from 100% to 40% in the group receiving the high dose. During the 2-month follow-up period after vancomycin therapy, global MRSA carriage increased from 25% to 55% in the group receiving the standard dose and decreased from 43% to 36% in the group receiving the high dose. CONCLUSION: Therapy with a high dose of vancomycin contributes to the sustained eradication of MRSA carriage without promoting the emergence of glycopeptide resistance.