In individuals with diabetes, a log linear relationship exists between cholesterol levels and cardiovascular disease. Type 2 diabetes (T2D) and Statins, a cholesterol lowering drug, have a complex relationship. Statins are potent modulators of CYP3A4 2 enzyme and endothelial nitric oxide synthase (eNOS) functions in a number of cholesterol-independent, cardio protective actions in T2D. The aim of this study was to evaluate the CYP3A4 2 and eNOS gene mutations in a large number of T2D patients undergoing statin treatments. Blood samples were collected from 386 subjects in which 196 diabetic patients with hyperlipidemia were undergoing statin treatment (108 females and 88 males). The 190 healthy non-diabetic volunteers formed the control group. We investigated single nucleotide polymorphisms in diabetic patients and controls, and found that the statin therapy was not found to be effective in lowering LDL-cholesterol levels. Statistical analysis showed that T2D patients had significantly higher values of not only glucose levels but also a very high value of Triglycerides and cholesterol at the time of presentation. Our results for CYP3A4 2 showed that the genotype TT (wild type) had lower LDL when compared to TC (heterozygous). Similarly, the genotype TC (heterozygous) had lower LDL when compared to CC (homozygous). A similar trend was observed in the GG (wild type) and GT (heterozygous) of eNOS. In conclusion, we have described for the first time a significant correlation of statin treatment and CYP3A4 2 and eNOS gene polymorphisms in T2D, suggesting a new genetic susceptibility factor for insulin resistance and hyperlipidemia in T2D.