OBJECTIVE: To analyse the efficiency of varenicline compared with bupropion, NRT (nicotine replacement therapy) and no pharmacological treatment in Spain. Methods: A Markov model was developed to analyse the health and economic consequences of smoking cessation therapies. The transition probabilities were taken from published studies. The model allows cost effectiveness analyses for different time frames (10 years, 20 years and life time). Outcomes are measured in terms of incremental life years gained (LYG) and QALYs. Pharmacological costs and costs of medical visits with varenicline and bupropion were considered. Treatment costs of smoking associated morbidity were taken from Spanish studies. RESULTS: The analyses were done under the perspective of the National Health System, discounting costs and health benefits at 3%. The life time cost-effectiveness analysis shows that varenicline dominates all other smoking cessation interventions (more effective at a lower cost). This is due to the higher efficacy of varenicline associated with a reduction in smoking related morbimortality, which, in the long term, accounts for health care cost savings that overcome the extra cost of varenicline. Even when shorter timeframes are considered (20 years), vareniclin is cost-effective in comparison with any other alternative. CONCLUSIONS: Varenicline is a dominant option (more effective at a lower cost) compared with all other smoking cessation treatments when the timeframe is the life span of the patient. Varenicline is cost-effective even when shorter timeframes are considered (20 years or more), with an estimated incremental cost per QALY far bellow any threshold commonly accepted in our environment.