Background: Platelets with high hemostatic activity play an important role in the pathophysiology of acute coronary syndrome (ACS), and mean platelet volume (MPV) has been proposed to be an indicator of platelet reactivity. We evaluated the predictive value of MPV and the responsive value of MPV with different antiplatelet agents in association with the clinical outcomes of ACS patients. Methods: A total of 1094 patients with ACS and 472 patients without ACSwere included. Blood sampleswere taken at hospital admission, at routine follow-up within one year, and beyond one year. The patients were divided into a “high MPV group” (> 9.0 fl, n = 305), “medium MPV group” (7.9-9.0 fl, n = 517), and “low MPV group” (< 7.9 fl, n = 272). The average follow-up time was 2.4 years, and the endpoints were major adverse cardiovascular events (MACEs) including all-cause mortality, time to recurrent ACS, target vessel re-intervention and stroke. Results: MPV was significantly higher in the patients with ACS than in those without ACS (8.6 ±1.1 vs. 8.4 ±1.0 fl, p = 0.007). MPV decreased in the following year (8.38 ±1.02 fl, p < 0.001) and also beyond one year (8.38 ±0.94 fl, p < 0.001) after ACS events. The changes in MPV were not significantly different between the patients receiving either clopidogrel or ticagrelor. The high MPV group had more cardiovascular risk factors and more MACEs than the low MPV group (p = 0.017). Conclusions: A higher MPV in patients with ACS was associated with more cardiovascular risk factors and more cardiovascular events during clinical follow-up.