Objective: Smoking influences several acute and chronic diseases within a population which might generate high medical costs in Korean health care. The aim of this study is to evaluate the cost-effectiveness of Varenicline compared with other smoking cessation interventions: bupropion, NRT(Nicotine Replacement Therapy), and unaided cessation (willpower) in smokers who attempt to quit. Methods: A Markov model was developed from a societal perspective to estimate long-term health benefit, smoking cessation cost, and co-morbidity-related cost. The model simulates cost and outcomes in a hypothetical cohort of current smokers attempting to quit during their lifetime with a 5% discount rate. The Markov cycle length is one year. The model includes six-potential co-morbidities: chronic obstructive pulmonary disease, ischemic heart disease, stroke, lung cancer, liver cancer, and gastric cancer. Transition probabilities were obtained from Korean epidemiologic data, whereas non-smoking rates after treatment, smoking relapses rates, and relative risk of above diseases were based on the published literature. Quality-adjusted life years (QALYs) were estimated as an effectiveness measure. Resource utilization and costs were calculated with public institutional data. One-way sensitivity analyses were performed on crucial parameters (discount rate, time horizons, mortality rate, costs, and utility weight). Results: As incremental cost-effectiveness ratio (ICER) for varenicline & bupropion is lower than that of bupropion & NRT, bupropion is subject to extended dominance. With the exclusion of bupropion, ICER for vareniciline vs. NRT was analyzed as US$5096 per quality-adjusted life year (QALY) during the life time. The results of sensitivity analysis showed quite stable across most of the included parameters. Conclusion: Varenicline costs US$5096 more to gain an additional QALY compared to NRT. Even though the threshold for ICER is not yet decided in Korea, varenicline can be regarded as a cost-effective alternative in the long term for the management of smoking cessation based on the UK & Australian experience.