OBJECTIVES: To evaluate the cost-effectiveness of varenicline compared to bupropion and nicotine-replacement therapy (NRT) from a third-party payer (Social Insurance Fund) perspective in Greece. METHODS: The Benefits of Smoking Cessation on Outcomes (BENESCO) Markov model was applied to calculate the long-term health and economic benefits of smoking cessation, simulating the incidence and outcomes of smoking-related morbidities to a hypothetical cohort of patients (age- and gender-representative of the Greek population) making a single quit attempt. Demographic, epidemiological, treatment efficacy and economic inputs for the modelled cohort were obtained from the literature and publicly available data from public healthcare databases. The model calculated costs and outcomes for a lifetime perspective, discounted at a 3% discount rate and reported in year 2011 fees and prices. Extensive probabilistic sensitivity analysis was performed to test the robustness of the results. RESULTS: The cohort consisted of 819,709 current smokers making a quit attempt. The respective 1year continuous abstinence rates were 22.5%, 15.5% and 15.4% for quitters under varenicline, NRT and bupropion. For a lifetime horizon, varenicline prevented in total 7652 and 7609 additional cases of smoking-related disease (coronary heart disease, stroke, lung cancer, chronic obstructive pulmonary disease) versus NRT and bupropion, respectively. Moreover, varenicline led to a gain of 21,219 QALYs (16,955 life years) and 21,099 QALYs (16,859 life years) for the cohort, compared to NRT and bupropion. Taking direct costs into account, varenicline produced cost-savings against both comparators for the lifetime as well as for shorter (20year) timeframes of analysis. The probabilistic sensitivity analysis corroborated the study outcomes. CONCLUSIONS: Taking into account the Social Security perspective in Greece, varenicline was a dominant smoking cessation strategy compared to NRT and bupropion, reducing both treatment costs and smoking-related morbidity.