OBJECTIVES: Smoking is associated with several acute and chronic diseases in adult population that generate high medical costs in the Mexican Health System. The purpose of the study was to model the long term economic and health consequences of two smoking cessation interventions (SCI) in Mexican smokers attempting to quit from the healthcare payer's perspective. METHODS: A cost–effectiveness assessment was developed using a Markov modeling approach adapted to the Mexican smoker population. The model simulates costs and effectiveness outcomes in a twenty-year period (1-year cycle) and includes four potential comorbidities: chronic obstructive pulmonary disease, lung cancer, coronary heart disease and stroke. Comparators were: varenicline vs. nicotine patches, both in a twelve-week treatment. Transition probabilities were obtained according to Mexican epidemiologic data. Quit successful rates, smoking relapses rates and relative risk of smoking associated to the mentioned comorbidities were obtained from clinical trials published in the literature. Effectiveness measure was the number of life-years gained (LYG). Resource use and costs data was obtained from representative published Mexican institutional databases (only direct medical costs were included). Costs and effectiveness measures were discounted 3% annually. Probabilistic sensitivity analysis was performed and acceptability curves were constructed. RESULTS: Varenicline, in a 20-year period analysis, showed that could generate 132,304 more quitters (4.9%); 4,905 less subjects with comorbidities (1.5%); 3,333 deaths avoided; and 22,598 LYG in comparison to the treatment with nicotine patches. Also, varenicline was in the long term a cost-saving strategy (expected cost reduction of US$10.6 millions – CI 95% US$9.8-US$11.7 millions). Results were robust to Monte Carlo second order sensitivity analysis and acceptability curves showed the same results with a mean of 70% of certainty. CONCLUSION: Despite its higher cost in the Mexican market, varenicline was the SCI most cost–effective in the long term for the management of patients attempting to quit.