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Background: Determining risk factors for acquisition of methicillin-resistant Staphylococcus aureus (MRSA) in hospitals is important for defining infection-control measures that may lead to fewer hospital-acquired infections., Objective: To determine patient-associated risk factors for acquisition of MRSA in a tertiary care hospital with the goal of identifying modifiable risk factors., Methods: A retrospective matched case-control study was performed. Case patients who acquired MRSA during hospitalization and 2 matched control patients were selected among inpatients admitted to target units during the period from 2001 through 2008. The odds of exposure to potential risk factors were compared between case patients and control patients, using matched univariate conditional logistic regression. A single multivariate conditional logistic regression model identifying independent patient-specific risk factors was generated., Results: A total of 451 case patients and 866 control patients were analyzed. Factors positively associated with MRSA acquisition were as follows: target unit stay before index culture; primary diagnosis of respiratory disease, digestive tract disease, injury or trauma, or other diagnosis compared with cardiocirculatory disease; peripheral vascular disease; mechanical ventilation with pneumonia; ventricular shunting or ventriculostomy; and ciprofloxacin use. Factors associated with decreased risk were receipt of a solid-organ transplant and use of penicillins, cephalosporins, rifamycins, daptomycin or linezolid, and proton pump inhibitors., Conclusion: Among the factors associated with increased risk, few are modifiable. Patients with at-risk conditions could be targeted for intensive surveillance to detect acquisition sooner. The association of MRSA acquisition with target unit exposure argues for rigorous application of hand hygiene, appropriate barriers, environmental control, and strict aseptic technique for all procedures performed on such patients. Our findings support focusing efforts to prevent MRSA transmission and restriction of ciprofloxacin use.