OBJECTIVES: A recent multi-country clinical trial of complicated skin and soft-tissue infections (cSSTI) due to proven or suspected methicillin-resistant Staphylococcus aureus (MRSA) demonstrated superior efficacy with linezolid compared with vancomycin. In this study, we estimated whether treatment with linezolid was also cost-effective versus vancomycin in patients with cSSTI. METHODS: All 1180 patients from the clinical trial (592 linezolid, 588 vancomycin) admitted to hospitals in 16 countries with cSSTI due to suspected or proven MRSA were studied. Costs of hospitalization for each patient were estimated by applying country-specific 2003 per diem hospital costs for days in the medical/surgical, intensive care, or the step-down units. Costs of intravenous (IV) therapy were applied to the duration of IV treatment plus administration costs. Medications were valued at wholesale acquisition cost. Medical resource costs from available countries were used before converting to US dollars using purchasing power parity adjustments. Furthermore, both costs and outcomes were risk adjusted using multivariate methods to account for patient population differences between countries. The cost effectiveness was measured as incremental cost per additional patient cured. RESULTS: There were no significant differences at baseline in clinical and demographic characteristics between the linezolid and vancomycin groups. Average risk-adjusted cost for patients treated with linezolid was $3629 versus $4140 (P <0.0001) for patients treated with vancomycin. In addition, the predicted cure rate for the linezolid group was 92% compared with 88% for the vancomycin group (P <0.0001). The lower costs for patients treated with linezolid were attributable to the switch to oral therapy and earlier hospital discharge. CONCLUSIONS: A higher cure rate in combination with lower overall treatment costs distinguishes linezolid as a dominant therapy option compared with vancomycin in patients with proven or suspected MRSA cSSTI.