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The oxidation of low-density lipoproteins and cell membrane lipids is believed to play an integral role in the development of fatty streak lesions, an initial step in coronary artery disease (CAD). Paraoxonase-1 (PON1) is an enzyme associated with the high-density lipoprotein (HDL) particle. PON1 protects LDL from oxidative modification by hydrolyzing lipid peroxides, suggestive of a role for PON1 in the development of CAD. The present study tested the hypothesis that Paraoxonase-1 promoter polymorphism T(-107)C could be a risk factor for severity of CAD in Iranian population. Paraoxonase-1 promoter genotypes were determined in 300 consecutive subjects (> 40 years old) who underwent coronary angiography (150 subjects with >50% stenosis served as cases [CAD+] and 150 subjects with < 20% stenosis served as controls [CAD-]). PON1 promoter genotypes were determined by PCR and BSTU1 restriction enzyme digestion. CAD+ Subjects did not show any significant differences in the distribution of PON1 promoter genotypes as compared to CAD- Subjects (P = 0.075). However the analysis of PON1 promoter genotypes distribution showed a higher percentage of (-107) TT among CAD+ compared with CAD- (P = 0.027). After controlling for other risk factors, the T(-107)C polymorphism had interaction with age (P = 0.012), but did not show any interaction with other risk factors such as BMI ,gender, smoking, diabetes, level of HDL-C, LDL-C, triglyceride and Total cholesterol. These data suggest that the TT genotype may represent a genetic risk factor for Coronary artery disease in Iranian population.