OBJECTIVES: Linezolid, an oxazolidinone antibiotic, has been shown to be effective in the treatment of complicated skin and soft-tissue infections (cSSTI) and nosocomial pneumonia (NP) including ventilator-associated pneumonia (VAP) caused by methicillin-resistant Staphylococcus aureus (MRSA) in hospitalized patients. However, hospital use of linezolid has been limited by high acquisition cost compared with other antibiotics. The objective was to compare the consistency of cost-effectiveness findings of linezolid across different health care systems. METHODS: Separate studies were conducted in Brazil, Italy, Germany, Spain, and the US to estimate the cost-effectiveness of linezolid for the treatment of gram-positive infections. In all studies (except US), a decision-analytic model was used to predict the cost-effectiveness of linezolid vs vancomycin or teicoplanin in each country. For the US, resource use data were obtained from a multicenter trial. For all other countries, clinical efficacy data were obtained from multinational clinical trials, cost data were based on published literature and local government sources, and a Delphi panel comprising local experts provided input into health care resource utilization data. RESULTS: In all health care systems, linezolid was cost-effective due to its superior clinical cure and survival (in NP). In cSSTI, total treatment costs were less expensive by $153 (Germany), $787 (Spain) and $873 (US) mainly due to reduction in length of stay. In Italy, treatment costs were similar (linezolid was $77 more). In VAP, cost per life year saved was $380 in Spain and cost saving in Brazil. Similarly, cost for life year gained for NP was $460. CONCLUSION: All studies showed that despite higher acquisition cost, linezolid is either cost-saving or cost-effective for hospitalized patients with gram-positive infections across multiple health care systems due to its higher clinical efficacy in terms of cure and survival rates.