Aims: New P2Y(12) adenosine diphosphate receptor antagonists have been used in the treatment of acute coronary syndrome (ACS) with different results. This systematic review analyzed and compared the evidence from large, clinical trials regarding the efficacy of clopidogrel relative to that of cangrelor, prasugrel, and ticagrelor in reducing the incidence of cardiovascular events in patients with ACS.Methods and Results: This analysis compared newer P2Y(12) inhibitors with clopidogrel of 13 clinical trials involved a total of 87,985 patients with ACS. The newer P2Y(12) inhibitors include cangrelor, prasugrel, and ticagrelor. Newer P2Y(12) inhibitors significantly decreased the risk of myocardial infarction and showed a trend toward reduction of cardiovascular death (odds ratio [OR] = 0.86, 95% confidence interval [CI], 0.77-0.96, and I-2 = 54%, P, 0.05); (OR = 0.85, 95% CI, 0.77-0.93, and I-2 = 42%, P, 0.001). The rates of stroke events and the incidence in patients with ACS did not differ statistically between the clopidogrel group and the group with newer P2Y(12) inhibitors (OR = 0.95, 95% CI, 0.79-1.14, and I-2 = 0%, P = 0.57). However, newer P2Y(12) inhibitors showed a significant increase in thrombosis in MI major or minor bleeding (OR = 1.21, 95% CI, 1.03-1.42, and I-2 = 56%, P - 0.02) compared with clopidogrel.Conclusions: Based on this meta-analysis, newer P2Y(12) inhibitors were significantly more effective than clopidogrel in the events of myocardial infarction and cardiovascular death in patients with ACS, although the incidence of thrombosis in MI-defined bleeding was higher compared with clopidogrel.