Coronary artery disease (CAD) also known as coronary heart disease is one of the leading causes of death and disability worldwide. Genetic and environmental factors play an important role in the pathogenesis and progression of CAD. The aim of this study was to evaluate the combined contribution of 3 gene polymorphisms to the risk of CAD and gene–gene interaction in the south Indian population. In this case-control study, 200 cases of CAD and 200 healthy controls were recruited. We studied 3 well known genetic polymorphisms of MTHFR (C677T; rs1801133), PON1 (Q192R; rs662) and ACE (I/D: rs4646994) in relation to CAD in South Indian population. Polymerase chain reaction (PCR) was carried out and followed by the restriction fragment length polymorphism and agarose gel electrophoresis. Genotypes of MTHFR C677T, CT and CT+TT, and PON1 Q192R QR were associated with the risk of CAD (C677T CT+TT vs CC: odds ratio [OR] = 3.3, 95% confidence intervals [CI] = 1.8–6.2; p = 0.00001), (CT vs CC: OR = 3.2, 95%CI = 1.8–5.6; p = 0.00003), and (Q192R QQ vs QR: OR = 2.1, 95%CI = 1.1–3.9; p = 0.03). The allele frequencies for T vs C: OR = 3.1, 95%CI = 1.8–5.3; p = 0.00001 and R vs Q: OR = 1.3, 95% CI = 1.0–1.7 p = 0.03. Multifactor dimensionality reduction (MDR) analysis was carried out with the combination of three genes and the results indicate that MDR analysis showed that, PON1 gene polymorphism formed a significant model in predicting the CAD risk in south Indian population.