Methicillin-resistant Staphylococcus aureus (MRSA) emerged as a clinically relevant human pathogen more than 5 decades ago. The virulent bacterium was first detected in hospitals and other health care facilities where vulnerable hosts, frequent exposure to the selective pressure of intensive antimicrobial therapy, and the necessity for invasive procedures created a favorable environment for dissemination. MRSA emerged as an important cause of health care-acquired infections, particularly central line-associated bloodstream infection, ventilator-associated pneumonia, and surgical site infection. Despite the adoption of infection control measures, the incidence of MRSA infection at most hospitals in the U.S. steadily increased for many years, but is now decreasing. Routine clinical cultures may miss a large portion of patients who are silent carriers of these organisms and serve as reservoirs for further transmission. More aggressive measures have been sought to check the spread of this particularly virulent pathogen. Active surveillance screening for MRSA is receiving greater attention for its potential value in identifying carriers of MRSA to prevent further transmission. To identify the population of colonized individuals, microbiological samples are obtained from at-risk patients even in the absence of signs or symptoms of infection. The screening strategy may use a testing modality with a rapid turnaround time. Because screening alone is not expected to affect health outcomes, screening strategies may include screening with or without isolation and with or without attempted decolonization or eradication. A Comparative Effectiveness Review was prepared by the Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center on Screening for Methicillin-Resistant Staphylococcus aureus (MRSA). The objective of the review was to synthesize comparative studies that examined the benefits or harms of screening for MRSA carriage in the inpatient or outpatient settings. The review examined MRSA-screening strategies applied to all hospitalized or ambulatory patients (universal screening), as well as screening strategies applied to selected inpatient or outpatient populations (e.g., patients admitted to the intensive care unit (ICU), patients admitted for a surgical procedure, or patients at high-risk of MRSA colonization or infection such those on prolonged antibiotic therapy) and compared them to no screening or to screening of selected patient populations (targeted screening). The review evaluated MRSA-screening strategies with or without isolation and with or without attempted eradication/decolonization. The review identified a number of limitations in the evidence that prevents precise estimates of the comparative effectiveness of screening for MRSA-carriage on infection rates, morbidity and mortality. Insufficient numbers of patients were enrolled in studies to be adequately powered to detect the effect of screening for MRSA-carriage compared with no screening or to screening of selected patient populations on morbidity and mortality. Studies failed to take a more uniform approach to the testing strategy used, address test turn-around time, or account for the management of patients before screening test results are known. The existing evidence failed to quantify and account for the potential bias introduced by secular trends that may contribute to variation in the incidence of infectious diseases over time. The evidence failed to account for the influence of concomitant infection prevention strategies and treatment interventions or staff compliance with them. Lacking such a standard, a maximally transparent approach to reporting interventions and potential confounders would be absolutely critical.