Introduction: Diabetic foot infections (DFIs) are the leading cause of non-traumatic lower extremity amputations in the United States. Antimicrobials active against methicillin-resistant Staphylococcus aureus (MRSA) are recommended in patients with associated risk factors; however, limited data exist to support these recommendations. Due to the changing epidemiology of MRSA, and the consequences of unnecessary antibiotic therapy, guidance regarding the necessity of empirical MRSA coverage in DFIs is needed. We sought to 1) describe the prevalence of MRSA DFIs at our institution and compare to the proportion of patients who receive MRSA antibiotic coverage and 2) identify risk factors for MRSA DFI. Methods: This was a retrospective cohort study of all adult, culture-positive DFI patients managed at University Hospital, San Antonio, TX between January 1, 2010 and September 1, 2014. Patient eligibility included a principal ICD-9-CM discharge diagnosis code for foot infection and a secondary diagnosis of diabetes. The primary outcome was MRSA identified in the wound culture. Independent variables assessed included patient demographics, comorbidities, prior hospitalization, DFI therapies, prior antibiotics, prior MRSA infection, and laboratory values. Multivariable logistic regression was used to identify risk factors for MRSA DFI. Results: Overall, 318 patients met inclusion criteria. Patients were predominantly Hispanic (79%) and male (69%). Common comorbidities included hypertension (76%), dyslipidemia (52%), and obesity (49%). S. aureus was present in 46% of culture- positive DFIs (MRSA, 15%). A total of 273 patients (86%) received MRSA antibiotic coverage, resulting in 71% unnecessary use. Male gender (OR 3.09, 95% CI 1.37-7.99) and bone involvement (OR 1.93, 1.00-3.78) were found to be independent risk factors for MRSA DFI. Conclusions: Although MRSA was the causative pathogen in a small number of DFI, antibiotic coverage targeted against MRSA was unnecessarily high.