Vancomycin and linezolid minimum inhibitory concentrations (MICs) were determined via Etest for 171 isolates of methicillin-resistant Staphylococcus aureus (MRSA) from 5 New York City area hospitals, with a 5000-patient Monte Carlo simulation performed for pharmacodynamic analysis. Pharmacodynamic targets, area under the concentration-time curve (AUC) to MIC (AUC/MIC) ratios, were >345 for vancomycin and >82.9 for linezolid. Parameters were based on AUC/MIC associated with clinical success for vancomycin in patients with pulmonary infections and bacteriostatic effect for linezolid in a neutropenic murine thigh infection model. MRSA, 98.8% and 99.4%, was susceptible to vancomycin (MIC50/MIC90, 2/2 μg/mL) and linezolid (MIC50/MIC90, 1/1 μg/mL), respectively. Cumulative fractions of response were 3%, 27%, and 92% for vancomycin 1000 mg every 12 hours, every 8 hours, and linezolid 600 mg every 12 hours, respectively. Methicillin-resistant S. aureus with vancomycin MIC >1 μg/mL predominated, with a resulting decrease in the probability of achieving pharmacodynamic exposure. Linezolid MICs were unaffected by increased vancomycin MICs and retained optimal pharmacodynamic target attainment.