OBJECTIVES: In patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI), the TRITON-TIMI 38 trial (TTT) demonstrated that treatment with prasugrel vs. clopidogrel significantly reduced rates of atherothrombotic events, though with increased risk of bleeding.  We evaluated the long-term cost-effectiveness of this approach in patients free of stroke or TIA, from the perspective of the UK National Health Service. METHODS: A Markov model was developed based on risk equations for cardiovascular death, myocardial infarction (MI) or stroke, bleeding, and rehospitalisation, derived from TTT (N=13,608 patients). Hospital readmissions captured during the trial in all patients from 8 countries (N=6,705) were assigned to UK diagnosis related groups.  After 12 months, common rehospitalisation costs were modelled to accrue over the life-time time horizon. RESULTS: During the first year incremental drug cost of prasugrel (+£162/patient) was partially offset by hospital cost savings (-£14/patient) due principally to reduced revascularization rates. Over the longer-term, prasugrel was associated with higher total costs resulting from rehospitalisations among survivors, of +£169/patient, with life expectancy gains of 0.06 years primarily due to reduced rate of MI, and  0.05 additional QALYs. Incremental cost per life year gained and per QALY gained were £2,606 and £3435 respectively. These results were consistent across subgroups, with incremental costs per QALY gained of £4494 in UA/NSTEMI, £2167 in STEMI, and £3461 in patients without any of three risk factors for bleeding (prior TIA/stroke, weight<60kg, age≥75 years). Probabilistic sensitivity analysis indicated a 72% probability of prasugrel being cost-effective compared with branded clopidogrel at a willingness to pay of £20,000 per QALY. CONCLUSIONS: Prasugrel treatment to 1 year in ACS-PCI patients appears cost-effective compared with branded clopidogrel.