Objective. Estimate smoking-attributable direct medical costs in Latin American health systems. Methods. A microsimulation model was used to quantify financial impact of cardio-vascular and cerebrovascular disease, chronic obstructive pulmonary disease (COPD), pneumonia, lung cancer, and nine other neoplasms. A systematic search for epidemiological data and event costs was carried out. The model was calibrated and validated for Argentina, Bolivia, Brazil, Chile, Colombia, Mexico, and Peru, countries that account for 78% of Latin America's population; the results were then extrapolated to the regional level. Results. Every year, smoking is responsible for 33 576 billion dollars in direct costs to health systems. This amounts to 0.7% of the region's gross domestic product (GDP) and 8.3% of its health budget. Cardiovascular disease, COPD, and cancer were responsible for 30.3%, 26.9%, and 23.7% of these expenditures, respectively. Smoking-attributable costs ranged from 0.4% (Mexico and Peru) to 0.9% (Chile) of GDP and from 5.2% (Brazil) to 12.7% (Bolivia) of health expenditures. In the region, tax revenues from cigarette sales barely cover 37% of smoking-attributable health expenditures (8.1% in Bolivia and 67.3% in Argentina). Conclusions. Smoking is responsible for a significant proportion of health spending in Latin America, and tax revenues from cigarette sales are far from covering it. The region's countries should seriously consider stronger measures, such as an increase in tobacco taxes.