Background: Human paraoxonase-2(PON2) which is exclusively intracellular possesses unique properities that distinguish it from PON1 and PON3. Recently, it was demonstrated that PON2 protects against atherosclerosis by preventing LDL oxidation. Emerging evidences have proposed that genetic variations in the PON2 gene may be associated with coronary artery disease (CAD). Objectives: To investigate the relationship between a common PON2 gene (Cys³¹¹-Ser) polymorphism and the presence and extent of CAD. Methods: The study comprised 112 patients recruited from those undergoing coronary angiography for suspected CAD, who were divided according to the presence or absence of CAD into 2 groups Group I including 62 patients with CAD and Group II including 50 patients proved to have normal coronaries. All the subjects included in the study were genotyped for the (Cys³¹¹-Ser) polymorphism of PON2 gene using RCR-RFLP. Results: The frequency of Cys allele was significantly higher in group I compared to Group II (77.4% vs. 56% respectively, P < 0.01). Patients with vessel score 3 had significantly higher severity score and higher Cys allele frequency than patients with vessel score 2, the latter group had also significantly higher severity score and Cys allele frequency than patients with vessel score 1. In multivariate logistic regression analysis of different variables for prediction of CAD, age [OR 3.79, CI (1.33 - 12.7), P < 0.01], smoking [OR 0.71, CI (0.23 - 7.81), P < 0.001], and PON2³¹¹ Cys allele [OR 5.67, CI (1.99 - 14.77), P < 0.001] were significantly independent predictors of CAD. Conclusion: Cys allele of PON2 311 gene polymorphism is an independent risk factor for CAD and it is associated not only with the presence of CAD but also with its extent and severity.