The present study aimed to determine the frequency of methicillin-resistant Staphylococcus aureus (MRSA)-positive clinical culture among hospitalized adults in different risk categories of a targeted MRSA active surveillance screening program and to assess the utility of screening in guiding empiric antibiotic therapy. We completed a prospective cohort study in which all adults admitted to non-intensive-care-unit locations who had no history of MRSA colonization or infection received targeted screening for MRSA colonization upon hospital admission. Anterior nares swab specimens were obtained from all high-risk patients, defined as those who self-reported admission to a health care facility within the previous 12 months or who had an active skin infection on admission. Data were analyzed for the subcohort of patients in whom an infection was suspected, determined by (i) receipt of antibiotics within 48 h of admission and/or (ii) the result of culture of a sample for clinical analysis (clinical culture) obtained within 48 h of admission. Overall, 29,978 patients were screened and 12,080 patients had suspected infections. A total of 46.4% were deemed to be at high risk on the basis of the definition presented above, and 11.1% of these were MRSA screening positive (colonized). Among the screening-positive patients, 23.8% had a sample positive for MRSA by clinical culture. Only 2.4% of patients deemed to be at high risk but found to be screening negative had a sample positive for MRSA by clinical culture, and 1.6% of patients deemed to be at low risk had a sample positive for MRSA by clinical culture. The risk of MRSA infection was far higher in those who were deemed to be at high risk and who were surveillance culture positive. Targeted MRSA active surveillance may be beneficial in guiding empiric anti-MRSA therapy.