Background One of the enzymes involved in the production of free radicals in atherosclerotic plaques is myeloperoxidase (MPO). There is a functional G/A polymorphism 463 bp upstream of the transcription start site of the enzyme with the G allele associated with a higher level of MPO expression than the A allele. Considering the potential role of MPO in the process of atherosclerosis, studying the relationship between this polymorphism and the incidence of coronary artery disease (CAD) seems reasonable. Method We performed a case-control study. The case group consisted of 229 patients who had angiographically proved atherosclerotic plaques in their coronary arteries. The control group consisted of 217 individuals who did not have a history of coronary artery disease, stroke, or peripheral vascular disease. Results We found that allele A of the MPO gene was less frequent in cases with CAD. In a recessive model patients with the AA genotype had a decreased risk of CAD (odds ratio 0.138, 95% confidence interval 0.040-0.474). In a dominant model a significant protective role for AA or AG versus GG was also detected (odds ratio 0.639, 95% confidence interval 0.436-0.937). Conclusion Our findings suggest that the –463 G/A polymorphism of the MPO gene influences the risk of CAD. This effect may be mediated by the effect of this polymorphism on the transcription level of the MPO gene. (Am Heart J 2001; 142:336-9.)