OBJECTIVES: Ventilator-associated pneumonia (VAP) is associated with increasing intensive care unit (ICU) admissions, morbidity and length of stay (LOS) as it’s one of the most common nosocomial infections in the ICU; raising overall costs. Literature suggests costs could be significantly reduced by using the most efficient empiric therapy. The aim of this study was to assess the cost-effectiveness (CE) of linezolid against generic vancomycin as an empiric therapy for adult VAP patients, from the public healthcare perspective.  METHODS: A cohort of patients with VAP in the ICU was simulated using a decision-tree model to compare costs and effectiveness of linezolid (600 mg/12 hours) and vancomycin (15 mg/kg/12 hours) (basecase). Effectiveness measures were: microbiological success rates, mortality rates, and ICU and ward LOS. The model used a 12-week time horizon and only direct medical costs were considered (inpatient costs, medication expenses, adverse events costs, hematologic and gastrointestinal tests) Effectiveness and epidemiologic data were retrieved from published literature.  Local costs (2012 US$) were gathered from the Social Security of Guatemala official databases. Monte Carlo probabilistic sensitivity analysis (PSA) was constructed. RESULTS: Linezolid resulted as the most effective and less expensive option for VAP adult patients. Clinical success rate was higher with linezolid (64.4%) against vancomicyn (56.1%).  Mean expected ICU LOS was 18 days for linezolid and 22 days for vancomycin, ward LOS was 9 and 10 days with linezolid and vancomycin, respectively.  Mortality rate was found lower in the linezolid arm (10.13%) in comparison to vancomycin (15.74%).  Overall costs per patient were $23,089.15 with linezolid and $26,384.63 with vancomycin.  In the CE incremental analysis, linezolid appeared as the cost-saving option. PSA outcomes support the robustness of these findings.  CONCLUSIONS: Linezolid resulted as the cost-saving therapy for treating VAP adult patients in ICU in Guatemala.