OBJECTIVES: Aldosterone blockers (AB) are recommended for use in heart failure (HF) and HF post acute myocardial infarction (AMI) in patients with left ventricular dysfunction. Although only eplerenone is licensed for post-AMI HF treatment, less expensive spironolactone is used in some clinical settings. This study aims to evaluate cost-effectiveness of eplerenone compared with spironolactone in Portuguese patients with HF post-AMI. METHODS: A Markov model was developed to predict life-years (LY), quality adjusted life-years (QALY) and associated costs of AB treatment over patients life time. Estimates of all cause mortality relative risks were obtained via a meta-regression of AB published trials. Transition probabilities were derived from EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Survival Study), adjusted by a Weibull function with meta-regression estimates. AB adverse events (hyperkalemia, gynescomatia) rates were derived from a published meta-analysis. AB class effect was assumed regarding non-fatal hospitalization rates. Resource use and discontinuation rates were elicited through a panel of six cardiologists with extensive clinical experience. Unit costs and other cause mortality rate were extracted from Portuguese official sources. Utilities were obtained using a regression model published in the literature derived from EPHESUS EQ-5D data. Societal perspective was adopted and both costs and effectiveness were discounted at 5%. RESULTS: Average cost per patient for eplerenone and spironolactone treatment were €25,907 and €20,963, respectively. Average effectiveness gained with eplerenone was 0.44LY and 0.41QALY, meaning the incremental cost-effectiveness ratios were €11,309/LY and €12,040/QALY. Although indirect comparison of eplerenone with spironolactone introduces some uncertainty for relative effectiveness and cost-effectiveness: probabilistic sensitivity analysis revealed eplerenone to be cost-effective in 59% of Monte Carlo iterations at a willingness to pay of €35,000/QALY. CONCLUSIONS: Compared with spironolactone, eplerenone treatment in patients with HF post-AMI is effective in reducing mortality, improving quality of life and is cost-effective by commonly used criteria in Portugal.