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Abstract: Aims: To assess the cost‐effectiveness of alternative smoking cessation scenarios from the perspective of the Spanish National Health Service (NHS). Design: We used the European study on Quantifying Utility of Investment in Protection from Tobacco model (EQUIPTMOD), a Markov‐based state transition economic model, to estimate the return on investment (ROI) of: (a) the current provision of smoking cessation services (brief physician advice and printed self‐helped material + smoking ban and tobacco duty at current levels); and (b) four alternative scenarios to complement the current provision: coverage of proactive telephone calls; nicotine replacement therapy (mono and combo) [prescription nicotine replacement therapy (Rx NRT)]; varenicline (standard duration); or bupropion. A rate of 3% was used to discount life‐time costs and benefits. Setting: Spain. Participants: Adult smoking population (16+ years). Measurements: Health‐care costs associated with treatment of smoking attributable diseases (lung cancer, coronary heart disease, chronic obstructive pulmonary infection and stroke); intervention costs; quality‐adjusted life years (QALYs). Costs and outcomes were summarized using various ROI estimates. Findings: The cost of implementing the current provision of smoking cessation services is approximately €61 million in the current year. This translates to 18 quitters per 1000 smokers and a life‐time benefit–cost ratio of 5, compared with no such provision. All alternative scenarios were dominant (cost‐saving: less expensive to run and generated more QALYs) from the life‐time perspective, compared with the current provision. The life‐time benefit–cost ratios were: 1.87 (proactive telephone calls); 1.17 (Rx NRT); 2.40 (varenicline‐standard duration); and bupropion (2.18). The results remained robust in the sensitivity analysis. Conclusions: According to the EQUIPTMOD modelling tool it would be cost‐effective for the Spanish authorities to expand the reach of existing GP brief interventions for smoking cessation, provide pro‐active telephone support, and reimburse smoking cessation medication to smokers trying to stop. Such policies would more than pay for themselves in the long run. [ABSTRACT FROM AUTHOR]