OBJECTIVES: According to DATASUS, from 1996 to 2005, there were more than 1 million hospitalizations related to smoking, with total costs sum of half billion dollars. The aim of this study was to assess the cost-effectiveness of varenicline compared to other existing strategies for smoking cessation in an adult population cohort from the public payer’s perspective. METHODS: The Benefits of Smoking Cessation on Outcomes (BENESCO) simulation model was used for an 18 years of age and older cohort of 557,881 smokers, within a lifetime time horizon. Smoking cessation therapies in comparison were: varenicline (0.5–2 mg/day), bupropion (300 mg/day), nicotine replacement therapy (NRT) (5-10 mg/day), and unaided cessation. Relapse rates were considered as 6.3% for the first 5 years after cessation, 2% for years 6 to 10 and 1% for subsequent years. Effectiveness measure was Life-Year gained (LYG). Smoking and smoking-related heath condition’s prevalence, resource use and costs data were obtained from DATASUS, INCA (National Cancer Institute), INCOR (Heart Institute) and DECIT (Science and Technology Department of Brazil). The model used a 5% discount rate for health outcomes and costs were expressed in 2010 USD. RESULTS: LYG for varenicline was 7310 compared to 7295 from bupropion, 7294 from nicotine replacement therapy and 7273 for untreated treatment. Compared to untreated patients, varenicline reduced smoking-related morbidity by 10,757 events, prevented 8,612 early deaths due to smoking related events, representing savings for US$139.602.241,20 from heathcare expenses. The net average cost per additional quitter showed that varenicline was cost-saving against bupropion (- USD 1.122,00) and nicotine replacement therapy (- US$ 46.184,40). CONCLUSIONS: Smoking cessation therapy with varenicline is cost-saving for Brazil. These results could help to reduce the tobacco related disease burden while agreeing with cost-containment policies.