Background: The dual antiplatelet therapy (DAPT) with aspirin and clopidogrel has been considered as the standard of care in the setting of acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI). Recent evidence supports a role of loss-of-function (LOF) variants in the CYP2C19 as a determinant of clopidogrel response. Carriers of the CYP2C19*2 LOF allele has found to have the reduced pharmacodynamic response to clopidogrel and worse clinical outcome as compared with non-carriers in Asian countries including Indian population. However, it is unknown whether the time course of the antiplatelet effects of clopidogrel differs according to CYP2C19 genotype in South Indian patients with ACS. Methods: We assessed the platelet reactivity in the early and late phases of ACS according to CYP2C19 genotypes. Eighty six consecutive in-patients who were admitted with ACS at our center were enrolled in the study. The determination of platelet aggregation was done by using a platelet aggregometer and genetic analysis was done by PCR-RFLP method. Results: The numbers of patients carrying the CYP2C19*1/*1 (extensive metabolizer, EM), *1/*2 (Intermediate metabolizer, IM), *2/*2 (poor metabolizer PM), genotypes were 22 (30.9%), 37 (52.1%), 12 (16.9%), respectively. Time course of platelet aggregation from baseline to the late phase among the 3 genotypes indicate that there was statistically significant at 30th day of treatment (p=0.004) between wild versus hetero and homozygous variant alleles. The percentage of patients shifted to prasugrel from clopidogrel due to non-response were 4 (8%), 11(29%), 6 (50%) in wild, heterozygous and homozygous variant alleles. In homozygous group, we found 4 out of 6 patients developed acute stent thrombosis within one week of PCI. Conclusion: We observed that the CYP2C19*2 and CYP2C19*1/*2 are the major determinants of clopidogrel efficacy. Acute stent thrombosis was observed in patients carrying CYP2C19*2 variant allele.