BACKGROUND Increased mortality, treatment failure, and hospital length of stay have been reported in patients treated with vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia when their isolates have a vancomycin minimum inhibitory concentration (MIC) > 1 μg/mL. Automated testing often fails to identify these isolates. We developed a simple clinical rule to predict vancomycin MIC of 2 μg/mL in patients with MRSA bacteremia. METHODS This cohort study was conducted at a tertiary care hospital and an affiliated acute rehabilitation facility. Consecutive patients with MRSA bacteremia from 2001 through 2007 were prospectively identified. Patient characteristics were examined for their association with high vancomycin MIC and a predictive model was created. RESULTS A total of 296 MRSA bacteremic episodes among 272 patients were identified; 19% of the episodes had isolates with a vancomycin MIC of 2 μg/mL. Variables associated with a vancomycin MIC of 2 μg/mL included older age (odds ratio [OR], 4.0; 95% confidence interval [CI], 1.5-10.4); prior vancomycin (OR, 3.8; 95% CI, 1.9-7.6) or daptomycin (OR, 7.9; 95% CI, 1.8-34.0) exposure; the presence of a nontunneled central venous catheter (OR, 1.9; 95% CI, 1.1-3.4) or prosthetic heart valve (OR, 3.6; 95% CI, 1.3-10.0); a history of MRSA bacteremia (OR, 3.0; 95% CI, 1.6-5.6); and the presence of sepsis (OR, 2.7; 95% CI, 1.4-5.1) or shock (OR, 2.2; 95% CI, 1.1-4.2) at the time of culture. The final predictive rule included age > 50 years (3 points), prior vancomycin exposure (2 points), history of MRSA bacteremia (2 points), history of chronic liver disease (2 points), and presence of a nontunneled central venous catheter (1 point). A score cutoff of ≥ 4 resulted in a sensitivity of 75% and specificity of 59% (negative predictive value, 91%; positive predictive value, 30%). CONCLUSIONS Several factors that predict high vancomycin MIC were identified, and a simple predictive tool was created to help clinicians determine which patients are likely to have MRSA isolates with high vancomycin MIC.