Background: The choice of antiplatelet therapy after acute coronary syndrome (ACS) is complicated: Ticagrelor and prasugrel are novel alternatives to clopidogrel, patients with some genotypes may not respond to clopidogrel, and low-cost generic formulations of clopidogrel are available. Objective: To determine the most cost-effective strategy for dual antiplatelet therapy after percutaneous coronary intervention for ACS. Design: Decision-analytic model. Data Sources: Published literature, Medicare claims, and life tables. Target Population: Patients having percutaneous coronary intervention for ACS. Time Horizon: Lifetime. Perspective: Societal. Intervention: Five strategies were examined: generic clopidogrel, prasugrel, ticagrelor, and genotyping for polymorphisms of CYP2C19 with carriers of loss-of-function alleles receiving either ticagrelor (genotyping with ticagrelor) or prasugrel (genotyping with prasugrel) and noncarriers receiving clopidogrel. Outcome Measures: Direct medical costs, quality-adjusted lifeyears (QALYs), and incremental cost-effectiveness ratios (ICERs). Results of Base-Case Analysis: The clopidogrel strategy produced $179 301 in costs and 9.428 QALYs. Genotyping with prasugrel was superior to prasugrel alone, with an ICER of $35 800 per QALY relative to clopidogrel. Genotyping with ticagrelor was more effective than genotyping with prasugrel ($30 200 per QALY relative to clopidogrel). Ticagrelor was the most effective strategy ($52 600 per QALY relative to genotyping with ticagrelor). Results of Sensitivity Analysis: Stronger associations between genotype and thrombotic outcomes rendered ticagrelor substantially less cost-effective ($104 800 per QALY). Genotyping with prasugrel was the preferred therapy among patients who could not tolerate ticagrelor. Limitation: No randomized trials have directly compared genotyping strategies or prasugrel with ticagrelor. Conclusion: Genotype-guided personalization may improve the cost-effectiveness of prasugrel and ticagrelor after percutaneous coronary intervention for ACS, but ticagrelor for all patients may be an economically reasonable alternative in some settings.