OBJECTIVES: To estimate the health benefits and cost-effectiveness of a polypill intervention (100mg aspirin, 20mg atorvastatin and 10mg ramipril) for the secondary prevention of cardiovascular (CV) events in adults with a history of myocardial infarction (MI) from the perspective of the Spanish health system compared with multiple monotherapy. METHODS: A Markov model was developed to estimate health outcomes, costs and incremental cost-effectiveness ratio (ICER) per LY gained and per QALY gained using a 10-year time horizon. The patient population included were men and women with an average age of 64.7 years, a history of MI and an indication for secondary prevention treatment. Patients in the model have a 3-month probability cycle to have one of the following five CV events: acute coronary syndrome, non-fatal stroke, non-fatal congestive heart failure requiring hospitalization, unplanned revascularization procedures, or (non-)CV death. Model inputs on efficacy, utility and adherence were obtained from systematic reviews. Different scenarios were modelled using different sources for acute event costs and alternative prices for polypill and its monocomponents. Probabilistic analyses were performed to test the robustness of the results. RESULTS: Polypill showed to prevent 45 CV fatal and non-fatal events per 1,000 patients in Spain in the base case. Total LYs and QALYs gained were 38 and 36 respectively, showing polypill was the dominant strategy. Probabilistic sensitivity analyses for the base-case assumptions showed a 90.1% chance of the polypill being cost-effective at a willingness-to-pay threshold of €30,000 per QALY gained compared with multiple monotherapy. Alternative scenario analyses showed that the polypill resulted to be dominant or cost-effective in all scenarios. CONCLUSIONS: The polypill intervention appears to be the dominant or cost-effective strategy versus its monocomponents taken separately, showing it can prevent fatal and non-fatal CV events in the Spanish population as well as to reduce healthcare costs.