BACKGROUND: Based on results of the PLATO (Platelet Inhibition and Patient Outcomes) trial comparing ticagrelor with clopidogrel therapy, the U.S. Food and Drug Administration approved ticagrelor in 2011 for reducing thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) with the proviso that it be taken with low-dose aspirin. OBJECTIVES: This study sought to assess the cost and cost effectiveness of ticagrelor therapy relative to clopidogrel in treating ACS patients from the perspective of the U.S. health care system. METHODS: We estimated within-trial resource use and costs using U.S. low-dose aspirin patients in PLATO (n = 547). Quality-adjusted life expectancy was estimated using the total PLATO population (n = 18,624), combined with baseline risk and long-term survival data from an external ACS patient cohort. Study drugs were valued at current costs. Cost effectiveness was assessed, as was the sensitivity of results to sampling and methodological uncertainties. RESULTS: One year of ticagrelor therapy, relative to that of generic clopidogrel, cost $29,665/quality-adjusted life-year gained, with 99% of bootstrap estimates falling under a $100,000 willingness-to-pay threshold. Results were robust to extensive sensitivity analyses, including variations in clopidogrel cost, exclusion of costs in extended years of life, and a recalibrated estimate of survival reflecting a lower underlying mortality risk in the United States. CONCLUSIONS: For PLATO-eligible ACS patients, a U.S. perspective comparison of the current standard of dual antiplatelet therapy of aspirin with clopidogrel versus aspirin plus ticagrelor showed that the ticagrelor regimen increased life expectancy at an incremental cost well within accepted benchmarks of good value for money. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872).