The most commonly studied polymorphic candidate genes for atherosclerosis are involved in lipid metabolism, hemostasis, fibrinolysis and inflammation. Genes affecting the function and tone of the artery have not been in the focus so far. Endothelial nitric oxide synthase (eNOS) and estrogen receptor á (ERá) are two strong candidate genes affecting vascular function. The products of these genes have been suggested to have important roles in the endothelium. Variation in these genes may affect the risk for coronary artery disease. The present study examined associations of ERá and eNOS gene polymorphisms with coronary artery disease and myocardial infarction in a Finnish male population (the Helsinki Sudden Death Study) and measured the genotype dependent effect of eNOS on coronary artery reactivity with positron emission tomography (PET) in a clinical series of healthy young men. Our findings suggest that the a-allele of the eNOS 4a/b polymorphism may be associated with protection from myocardial infarction. Moreover, statin treatment improves coronary reactivity by a mechanism that is eNOS genotype and adenosine -dependent. Pravastatin in subjects with eNOS a-allele may modulate coronary reactivity by increasing NO production by the endothelium or by affecting some other mechanisms in the coronary artery wall itself. This could have important consequences also in the course of myocardial infarction. We also found that the ERá gene might provide a candidate gene for coronary artery disease. Men in the HSDS with a long variant of the ERá gene and/or a mutated allele in exon 1 had a significantly greater severity of coronary artery disease than did men with other forms of the gene. They were also more susceptible to coronary thrombosis and myocardial infarction. To conclude, these studies suggest that ERá and eNOS genetic variations are associated in the mechanisms of coronary artery disease pathogenesis in men.