Hypertension is a result of interaction between complex environmental and genetic factors. The genes cytochrome (CYP) 2C8, CYP2C9, and CYP2J2 are involved in the metabolism of arachidonic acid, which releases endothelium derived hyperpolarizing factors responsible for mediating the smooth muscle relaxation. Aim: The study is aimed to analyze the association of CYP2C8, CYP2C9, and CYP2J2 gene polymorphisms with the risk of hypertension in the South Indian population. Methods and Results: The case-control study consisted of 279 hypertensive patients and 321 healthy controls aged ranges between 30 and 60 years. The deoxyribonucleic acid was extracted using standard phenol-chloroform method. Genotyping was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism and real-time-PCR methods. Multiple-logistic regression analysis was used to analyze the association between polymorphisms and the risk of hypertension. We did not observe any association of CYP2C8*2, CYP2C8*3, CYP2C9*2, CYP2C9*3, and CYP2J2*7 with hypertension. Conclusion: Our results suggest that CYP2C8*2, CYP2C8*3, CYP2C9*2, CYP2C9*3, and CYP2J2*7 are not associated with hypertension in South Indian population.