OBJECTIVES: Meticillin-resistant staphylococcus aureus (MRSA) is an important cause of antimicrobial-resistant healthcare-associated infections worldwide. Its prevalence remains high in the Greek hospital setting. Complicated skin and soft tissue infections (cSSTIs) due to MRSA are associated with prolonged hospitalization, additional costs of care and significant morbidity. The purpose of this study was to conduct a cost-effectiveness analysis of different treatment scenarios in the management of MRSA-cSSTIs, under a third-party payer perspective. METHODS: The model was based on a decision tree simulating costs and outcomes for a maximum of 28 days, consisting of empiric, first-line and second-line treatment, for patients with MRSA-cSSTIs. Inpatient and outpatient healthcare services were included in the analysis. Data on efficacy of the pharmacotherapies under evaluation were derived from a recent meta-analysis (Bassetti et al 2013) and resource use was elicited via an expert panel. Economic results, expressed in Euros (2013), reflect the Greek social insurance setting. RESULTS: Three different first→second line treatment scenarios (daptomycin→linezolid, linezolid→daptomycin, vancomycin→linezolid) were evaluated, as recommended by the expert panel. Total management costs per patient were €4,199, €3,809, and €3,900; quality adjusted life years (QALY) gained were 0.058, 0.059 and 0.057 respectively for the above scenarios. The scenario containing first-line linezolid proved to be a dominant therapeutic option versus the other scenarios (less costly, higher QALYs), whereas first-line daptomycin scenario did not appear to be cost-effective versus the respective vancomycin scenario (incremental cost-utility ratio €243,932) in the management of MRSA-cSSTIs. Second line oral linezolid was used as continuation treatment after failure/intolerance or switch from intravenous vancomycin and daptomycin. Second line intravenous daptomycin was assumed to be administered via an outpatient parenteral treatment service. CONCLUSIONS: Findings suggest that use of first-line linezolid in the management of MRSA-cSSTIs could result in savings for the third-party payer in Greece accompanied by enhanced quality of life results.