BACKGROUND Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of invasive surgical site infection (SSI) in the USA. Antimicrobial prophylaxis for SSI typically includes a cephalosporin. Vancomycin is used to provide MRSA coverage, but the timing of administration is challenging. Linezolid is an attractive agent for SSI prophylaxis, particularly for the prevention of SSI due to MRSA. METHODS We developed a decision-analytic model to evaluate linezolid use for cardiothoracic SSI prophylaxis. A theoretical cohort of 10,000 cardiothoracic surgery patients was followed through 2 stages: (1) occurrence of SSI, and (2) mortality after SSI. All patients were administered cefuroxime, vancomycin, or linezolid between 1 and 180 min prior to surgical incision. SSIs were categorized into 3 pathogen categories: (1) methicillin-susceptible Gram-positive, (2) methicillin-resistant Gram-positive, and (3) other organisms. The most effective strategy resulted in the fewest SSIs. Assumptions for antibiotic effectiveness, impact of administration time, and pathogens were based on the published literature. RESULTS Compared with cefuroxime, there was a 1% increase in the total number of SSIs in the linezolid group (mean SSI increase = 7), while there was a 12% increase in the vancomycin group (mean SSI increase = 86). Linezolid prophylaxis resulted in fewer SSIs due to methicillin-resistant Gram-positive infections (n = 108) compared with cefuroxime (n = 200, 46% reduction in the linezolid group) and vancomycin (n = 119, 9% reduction in the linezolid group). CONCLUSIONS This simulation indicates that linezolid may offer benefits for SSI prophylaxis over existing prophylactic agents, particularly for the prevention of SSI due to Gram-positive methicillin-resistant pathogens.