OBJECTIVES: The POPular Genetics trial demonstrated that a genotype-guided strategy to select antiplatelet therapy in patients with ST-segment elevation myocardial infarction (STEMI) compared to universal treatment with ticagrelor or prasugrel, resulted in a reduction in bleedings without an increase in the thrombotic risk. The objective of this analysis was to assess the cost-effectiveness of the genotype-guided therapy. METHODS: In the POPular Genetics trial STEMI patients who underwent primary percutaneous coronary intervention were randomized to an intervention or a control arm. In the intervention arm CYP2C19 genetic testing for the *2 and *3 loss-of-function alleles took place. Carriers of a loss-of-function allele were treated with ticagrelor or prasugrel, while noncarriers were treated with clopidogrel. In the control arm patients were treated with ticagrelor or prasugrel. An alongside clinical-trial cost-effectiveness analysis was conducted based on a decision-model with 1000 patients in both groups. A hybrid model, consisting of a 1-year decision tree combined with a 25-years Markov model was developed, to estimate the life-time cost-effectiveness from a societal perspective. Outcome measures were costs, quality-adjusted life-years (QALYs) and incremental cost per QALY gained. Deterministic and probabilistic sensitivity analyses were conducted to account for the uncertainty around the key parameters. In an exploratory analysis the price for ticagrelor and prasugrel was the same as clopidogrel, to simulate the effect of generic ticagrelor and prasugrel. RESULTS: The genotype-guided strategy resulted in 34.67 QALY gained with cost-savings of €641,420.82, indicating that the genotype-guided strategy is a cost-saving intervention. The exploratory analysis – keeping the price of antithrombotic therapies at the same price level – resulted in cost-savings of €177,594.15. Deterministic and probabilistic sensitivity analyses confirmed the robustness of the base-case analysis. CONCLUSIONS: Based on the POPular Genetics trial, a genotype-guided strategy compared to universal ticagrelor or prasugrel treatment resulted in favorable cost-effectiveness with QALYs gained and cost-savings.