OBJECTIVES Previous economic analyses of MRSA-confirmed cSSTI have not included costs related to outpatient parenteral antibiotic therapy (OPAT). The objective of this analysis was to develop an economic model to estimate medical and drug costs within both inpatient and outpatient components of care for treating MRSA cSSTI. METHODS A 4-week decision model was developed to estimate the direct total, inpatient, and outpatient costs of treating MRSA cSSTI from a U.S. payer perspective taking into account successes, failures, and adverse events (AEs). Comparators included vancomycin, linezolid, daptomycin, and tigecycline. Published literature and database analyses, with validation by experts, provided clinical inputs and resource use data including MRSA efficacy, length of stay (LOS), consequences of AEs and cSSTI failure, OPAT services, among others. Cost data was derived from literature and standard CPT coding reimbursements. The base case analysis assumed equal efficacy and equal LOS of 4 days among comparators. Univariate and probabilistic sensitivity analyses tested efficacy, complication rates, LOS, and other resource use parameters. Costs were reported in 2008US$. RESULTS Total drug acquisition costs were >4-6 times lower for vancomycin compared to tigecycline, linezolid, and daptomycin. However, the total 4-week cost of treatment including drugs, clinical failures, complications, and OPAT were lowest for linezolid ($8,149), followed by vancomycin ($8,974), tigecycline ($10,333), and daptomycin ($11,362). Oral linezolid reduced the outpatient medical costs by 10-fold versus IV comparators. The most sensitive model variables for total cost were the MRSA efficacy, hospital LOS, OPAT days, and line placement/complication costs. CONCLUSIONS Although total drug acquisition costs were lower for vancomycin vs. comparators, the model suggests linezolid provides total cost savings in cSSTI versus IV therapies, particularly in the outpatient arena. The budget impact of antimicrobials for cSSTI should consider total medical cost offsets from both inpatient and outpatient perspectives.