CONTEXT The relationship of platelet function testing measurements with outcomes in patients with acute coronary syndromes (ACS) initially managed medically without revascularization is unknown. OBJECTIVE To characterize the differences and evaluate clinical outcomes associated with platelet reactivity among patients with ACS treated with clopidogrel or prasugrel. DESIGN, SETTING, AND PATIENTS Patients with medically managed unstable angina or non-ST-segment elevation myocardial infarction were enrolled in the TRILOGY ACS trial (2008 to 2011) comparing clopidogrel vs prasugrel. Of 9326 participants, 27.5% were included in a platelet function substudy: 1286 treated with prasugrel and 1278 treated with clopidogrel. INTERVENTIONS Aspirin with either prasugrel (10 or 5 mg/d) or clopidogrel (75 mg/d); those 75 years or older and younger than 75 years but who weighed less than 60 kg received a 5-mg prasugrel maintenance dose. MAIN OUTCOME MEASURES Platelet reactivity, measured in P2Y12 reaction units (PRUs), was performed at baseline, at 2 hours, and at 1, 3, 6, 12, 18, 24, and 30 months after randomization. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke through 30 months. RESULTS Among participants younger than 75 years and weighing 60 kg or more, the median PRU values at 30 days were 64 (interquartile range [IQR], 33-128) in the prasugrel group vs 200 (IQR, 141-260) in the clopidogrel group (P < .001), a difference that persisted through all subsequent time points. For participants younger than 75 years and weighing less than 60 kg, the median 30-day PRU values were 139 (IQR, 86-203) for the prasugrel group vs 209 (IQR, 148-283) for the clopidogrel group (P < .001), and for participants 75 years or older, the median PRU values were 164 (IQR, 105-216) for the prasugrel group vs 222 (IQR, 148-268) for the clopidogrel group (P < .001). At 30 months the rate of the primary efficacy end point was 17.2% (160 events) in the prasugrel group vs 18.9% (180 events) in the clopidogrel group (P = .29). There were no significant differences in the continuous distributions of 30-day PRU values for participants with a primary efficacy end point event after 30 days (n = 214) compared with participants without an event (n = 1794; P = .07) and no significant relationship between the occurence of the primary efficacy end point and continuous PRU values (adjusted hazard ratio [HR] for increase of 60 PRUs, 1.03; 95% CI, 0.96-1.11; P = .44). Similar findings were observed with 30-day PRU cut points used to define high on-treatment platelet reactivity-PRU more than 208 (adjusted HR, 1.16; 95% CI, 0.89-1.52, P = .28) and PRU more than 230 (adjusted HR, 1.20; 95% CI, 0.90-1.61; P = .21). CONCLUSIONS Among patients with ACS without ST-segment elevation and initially managed without revascularization, prasugrel was associated with lower platelet reactivity than clopidogrel, irrespective of age, weight, and dose. Among those in the platelet substudy, no significant differences existed between prasugrel vs clopidogrel in the occurence of the primary efficacy end point through 30 months and no significant association existed between platelet reactivity and occurrence of ischemic outcomes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00699998.