BACKGROUND: Patients receive prophylactic antibiotics against surgical site infections (SSIs) before or during many procedures. Glycopeptide antibiotics are effective against most strains of methicillin-resistant Staphylococcus aureus (MRSA), but their wider use risks increasing resistance. Our objective was to review the evidence for clinical effectiveness that might help to determine whether there is a threshold of MRSA prevalence at which switching from non-glycopeptide to glycopeptide antibiotic prophylaxis might be justified. METHODS: We performed a systematic review of randomized trials comparing a glycopeptide with an alternative antibiotic regimen for SSI prophylaxis in adults undergoing clean or clean-contaminated surgical procedures. The evidence was used to inform development of a decision-analytic model. We subsequently updated the review to May 2008. RESULTS: Fourteen studies were identified that provided evidence concerning clinical effectiveness. The studies were too heterogeneous clinically for meta-analysis. Only one of 12 trials found that glycopeptides reduced SSIs significantly at 30 days compared with non-glycopeptide antibiotics. Of the two trials that reported on MRSA infection, neither found a significant difference between glycopeptide and comparator drugs. CONCLUSIONS: This systematic review did not find any evidence to support the use of glycopeptides in preference to other antibiotics for the prevention of MRSA infections and SSIs. The limitations of the evidence make it difficult to identify a threshold at which a switch from non-glycopeptide to glycopeptide prophylaxis should be recommended. Given the difficulties of addressing this issue through randomized trials, further research should focus on hospital infection control policies, MRSA screening, and the isolation and treatment of anyone infected with MRSA prior to surgery.