Varenicline is a nicotinic acetylcholine receptor partial agonist that is approved for use as an aid to smoking cessation. Randomized clinical trials show that its efficacy is superior to that of other current smoking cessation therapies. This study set out to determine the cost effectiveness of varenicline relative to other smoking cessation interventions (bupropion and nicotine replacement therapy [NRT]) as well as brief counselling alone and unaided cessation in a cohort of Belgian adult smokers making a one-time quit attempt, from the perspective of the healthcare payer (public and private).A Markov model, the Benefits of Smoking Cessation on Outcomes (BENESCO) model, was applied to calculate the long-term health and economic benefits of smoking cessation. Cost effectiveness was expressed as cost per life-year (LY) gained and cost per quality-adjusted life-year (QALY) gained. Clinical and economic model inputs were obtained from the literature and public healthcare databases. Costs were discounted at 3% and health outcomes at 1.5%. A probabilistic sensitivity analysis and a one-way sensitivity analysis were performed to test the robustness of the results.Varenicline is associated with a reduction of smoking-related morbidity and mortality as well as with a decrease in healthcare costs compared with the pharmacological agents bupropion and NRT. Varenicline also leads to additional LYs and QALYs compared with brief counselling alone and unaided cessation over a lifetime period. Varenicline is a dominant strategy compared with bupropion and NRT. Compared with brief counselling alone and unaided cessation, varenicline presents a cost/QALY of euro240 and euro1656, respectively.Varenicline is a cost-effective alternative to brief counselling and unaided cessation, and is a cost-saving treatment in comparison with bupropion and NRT, in a Belgian population of smokers willing to quit.