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Routine us of vancomycin for perioperative prophylaxis is discouraged, principally to minimize microbial resistance to it. However, outcomes and costs of this recommendation have not been assessed. We used decision-analytic models to compare clinical results and cost-effectiveness of no prophylaxis, cefazolin, and vancomycin, in coronary artery bypass graft surgery. In the base case, vancomycin resulted in 7% fewer surgical site infections and 1% lower all-cause mortality and saved $117 per procedure, compared with cefazolin. Cefazolin, in turn, resulted in substantially fewer infections and deaths and lower costs than no prophylaxis. We conclude that perioperative antibiotic prophylaxis with vancomycin is usually more effective and less expensive than cefazolin. Data on vancomycin's impact on resistance are needed to quantify the trade-off between individual patients' improved clinical outcomes and lower costs and the future long-term consequences to society.