OBJECTIVE To explore the economic impact to a hospital of universal methicillin-resistant Staphylococcus aureus (MRSA) screening. METHODS We used a decision tree model to estimate the direct economic impact to an individual hospital of starting universal MRSA screening and contact precautions. Projected costs and benefits were based on literature-derived data. Our model examined outcomes of several strategies including non-nares MRSA screening and comparison of culture versus polymerase chain reaction-based screening. RESULTS Under baseline conditions, the costs of universal MRSA screening and contact precautions outweighed the projected benefits generated by preventing MRSA-related infections, resulting in economic costs of $104,000 per 10,000 admissions (95% CI, $83,000-$126,000). Cost-savings occurred only when the model used estimates at the extremes of our key parameters. Non-nares screening and polymerase chain reaction-based testing, both of which identified more MRSA-colonized persons, resulted in more MRSA infections averted but increased economic costs of the screening program. CONCLUSIONS We found that universal MRSA screening, although providing potential benefit in preventing MRSA infection, is relatively costly and may be economically burdensome for a hospital. Policy makers should consider the economic burden of MRSA screening and contact precautions in relation to other interventions when choosing programs to improve patient safety and outcomes.