Cigarette smoking is a powerful risk factor for coronary artery disease (CAD), leading to the formation of DNA alterations within blood vessels and heart. However, the degree of smoking-related atherosclerosis varies from individual to individual. Genetic polymorphisms of relevant xenobiotic metabolising enzymes may determine the susceptibility of an individual response to environmental toxicants. The purpose of this study was to test the hypothesis that the inheritance of polymorphic genes encoding cytochrome P450 1A1 (CYP1A1 MspI) and glutathione S-transferases (GSTM1(null) and GSTT1(null)) may be causally associated with the presence and severity of smoking-induced CAD. In a case-only design, 222 (179 male, 57.8+/-10.3 years) consecutive smoker patients who had undergone elective and diagnostic coronary angiography were recruited. We found a group (n=169) of smoker patients with significant CAD, defined as>50% reduction in diameter of at least one major vessel, and a group without obstructive CAD (n=53). No significant differences were observed in CYP1A1 genotypes frequencies between CAD and non-CAD smokers (p=0.1). Homozygous deletion of GSTM1 had a frequency of 58.6% among patients with CAD and 45.3% among those without CAD (p=0.08). The frequency of the GSTT1(null) genotype was 43.8% among the patients with CAD and 24.5% among CAD-free subjects (p=0.01). After adjustment for traditional risk factors, the presence of combined GSTM1(null)GSTT1(null) genotypes was significantly associated with an increased risk of CAD (OR=3.9; 95% CI: 1.3-11.4, p=0.01). Moreover, smokers with combined GSTM1(null)GSTT1(null) genotypes had significantly higher number of stenosed vessels than those with the positive genotype (2.3+/-0.9 versus 1.7+/-0.8, p=0.03). Our findings showed that smokers carrying GST deleted genotypes have an increased susceptibility to the smoking related coronary artery disease. Exploring gene-smoking effect provides an excellent model in order to understand gene-environment toxicants interaction and its implications to cardiovascular disease.