Abstract Background Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of complicated skin and skin structure infections (cSSSI). Patients with MRSA require different empiric treatment than those with non-MRSA infections, yet no accurate tools exist to aid in stratifying the risk for a MRSA cSSSI. We sought to develop a simple bedside decision rule to tailor empiric coverage more accurately. Methods We conducted a large multicenter (N=62 hospitals) retrospective cohort study in a US-based database between April 2005 and March 2009. All adult initial admissions with ICD-9-CM codes specific to cSSSI were included. Patients admitted with MRSA vs. non-MRSA were compared with regard to baseline demographic, clinical and hospital characteristics. We developed and validated a model to predict the risk of MRSA, and compared its performance via sensitivity, specificity and other classification statistics to the healthcare-associated (HCA) infection risk factors. Results Of the 7,183 patients with cSSSI, 2,387 (33.2%) had MRSA. Factors discriminating MRSA from non-MRSA were age, African-American race, no evidence of diabetes mellitus, cancer or renal dysfunction, and prior history of cardiac dysrhythmia. The score ranging from 0 to 8 points exhibited a consistent dose–response relationship. A MRSA score of 5 or higher was superior to the HCA classification in all characteristics, while that of 4 or higher was superior on all metrics except specificity. Conclusions MRSA is present in 1/3 of all hospitalized cSSSI. A simple bedside risk score can help discriminate the risk for MRSA vs. other pathogens with improved accuracy compared to the HCA definition.