Several factors contribute to the development of coronary artery disease (CAD). Adenosine diphosphate (ADP) activated P2Y12 receptor also plays a key role in platelet activation and aggregation. It has been found that common variation in the P2Y12 gene was associated with increased platelet aggregation resulting in adverse cardiovascular outcomes. Thus, polymorphisms in the ADP receptor P2Y12 may contribute to the development of CAD. This study aims to determine the frequency distribution of platelet receptor polymorphism P2Y12 (i744T>C) in Tamilian population and to predict its possible role in CAD. Three hundred seventyone subjects were recruited comprising of 221 healthy volunteers and 150 patients with CAD belonging to either sex, aged 18-60 years of Tamilian origin. Genomic DNA was extracted using phenol-chloroform method. Genotyping was done by PCR-RFLP (Polymerase chain reaction-restriction fragment length polymorphism). The C allele frequency of P2Y12 polymorphism in controls and cases was 8.4% and 17.7%, respectively. The TT, TC, and CC genotype frequencies in controls and cases were 83.7%, 15.8%, 0.5% and 66.7%, 31.3%, 2%, respectively. The genotype frequencies were in HardyWeinberg equilibrium. There was a significant association (p < 0.05) between the mutant genotypes of P2Y12 (i744T>C) polymorphism and risk of CAD. The odds ratio was found to be 2.6. The variant allele frequency of P2Y12-i744T>C was significantly different from other populations. There was a significant association between the mutant genotypes of P2Y12 (i744T>C) polymorphism and risk of developing CAD. Thus, the present study will emphasize on the relevance of pharmacogenetic testing of P2Y12 (i744T>C) receptor gene polymorphism in CAD patients.