OBJECTIVES: . In Central American countries, the economic burden of tobacco has not been assessed. In Costa Rica, a study demonstrated that tobacco-related diseases represent high costs for the health system. The aim of this study was to assess the cost-effectiveness of varenicline compared to other existing strategies for smoking cessation within a 20-year time horizon in an adult population cohort from Central American and the Caribbean countries using the healthcare payer’s perspective. METHODS: . The Benefits of Smoking Cessation on Outcomes (BENESCO) simulation model was used for an adult cohort in Costa Rica, Panama, Nicaragua, El Salvador and Dominican Republic (n=19,429,581). Smoking cessation therapies compared were varenicline (0.5 – 2 mg/day) versus bupropion (300 mg/day); NRT (5-10 mg/day) and unaided cessation.  Effectiveness measures were: Life-Year gained (LYG) and quality-adjusted life-year gained (QALY’s). Resource use and costs data were obtained from country’s Ministry of Health and/or Social Security Institutions (2008-2009). The model used a 3% discount rate for costs (expressed in 2009 US dollars) and health outcomes. Probabilistic sensitivity analyses (PSA) were conducted and acceptability curves were constructed. RESULTS: . Varenicline reduced smoking-related morbidity, mortality and healthcare costs.  Mortality in the varenicline arm was reduced by 5,738, 7,425 and 14,007 deaths compared with bupropion, NRT and unaided cessation.  The net average cost per additional quitter showed that varenicline was cost-saving against competing alternatives.  The cost per additional quitter on varenicline was US$-269 compared with bupropion and US$2,624 compared with unaided cessation. Cost-effectiveness analyses showed that varenicline was the dominant strategy. At a willingness-to-pay of US$10,000/QALY, the probability that varenicline is cost-effective met 100%.  PSA results support the robustness of the findings. CONCLUSIONS: . Smoking cessation therapy with varenicline is cost-saving for Central American countries.  These results could help to reduce the tobacco related disease burden and align cost-containment policies.