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Objective: Genetics is a known factor in the susceptibility to cardiovascular disease. In this study, polymorphisms of endothelial nitric oxide synthase (eNOS) (T876C and G894T) and hypoxiainducible factor 1 (HIF1) (rs10873142 and rs41508050) in coronary artery disease were compared with healthy subjects, and the relationship between these mutations and risk of coronary artery disease (CAD) was assessed. Methods: Blood samples were collected from 138 patients with obstructive CAD and 115 healthy subjects. Polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP), Griess test, and enzyme-linked immunosorbent assay (ELISA) were used to measure serum nitric oxide (NO) and paraoxonase antioxidant. Independent t-test was used to examine the relationship between variables. Results: There was no significant difference between genotype frequency in healthy subjects and patients for eNOS and HIF1 alpha polymorphisms. There was no significant difference between these polymorphisms and age, sex, hypertension and lipidemia. Furthermore, the difference in mean serum levels of NO in different genotypes of the G894T gene was not significant between the patient and control groups. However, the difference in mean serum NO levels in different genotypes of the T786C gene was significant between the patient and control groups such that minimum and maximum serum NO levels were observed in individuals bearing TT and TC genotypes, respectively. The difference in mean serum NO levels was higher in patients than in controls, and was statistically significant. Conclusions: The results suggest that the T876C polymorphism could be associated with low serum NO level and implicated as a risk factor for developing CAD. Furthermore, our findings indicate that genetics may not be involved in susceptibility to CAD; however, further comprehensive studies are required.