Objective To study the pharmacogenomic-associated factors of clopidogrel antiplatelet reactivity in Han Chinese elderly patients with acute coronary syndrome(ACS). Methods During September 1st, 2011 to September 1st, 2012, ACS patients over 60 years were continuously enrolled from hospitalized patients in Institute of Geriatric Cardiology, Chinese PLA General Hospital, following strict inclusion criteria. All of the enrolled patients were prescribed with normal dose of aspirin and clopidogrel. The adenosine diphosphate (ADP)-induced platelet aggregation rate on the 5th day was determined by light transmission aggregation (LTA). SnapShot method was applied to detect candidate gene variants, which related with clopidogrel metabolism and activity (including PON1 Q129R, CYP2C19*2, CYP2C19*3, CYP2C19*17 and ABCB1 C3435T). Results In the total 246 enrolled ACS patients, univariate analysis showed that only CYP2C19*2 variant was significantly related with ADP-induced platelet aggregation rate after stable clopidogrel treatment (P＝0.001). The CYP2C19*2 carriers showed an obviously higher platelet aggregation rate compared with the non-carriers [(46.1±21.25)% vs (39.38±19.44)%, P＜0.001]. After adjusting the impact of age, gender, body mass index, comorbidities, concomitant medications and so on, stepwise multiple regression showed that CYP2C19*2 was still significantly related with ADP-induced platelet aggregation rate after stable clopidogrel treatment, which could explain 22.2% variance of clopidogrel antiplatelet reactivity variance (P＝0.001). Conclusion CYP2C19*2 is the major pharmacogenomic determinant which affects clopidogrel antiplatelet reactivity in Chinese Han elderly patients with acute coronary syndrome.