Oxidative stress plays a significant role in the pathogenesis of coronary artery disease (CAD). A p22(phox)-based NAD(P)H oxidase acts as a potent superoxide-generating system in the vasculature. We studied the association of the A640G and the C242T polymorphisms with clinical risk factors, endothelial function, and severity of CAD in a cohort of 216 patients referred for coronary angiography. The frequency of p22(phox) genotypes for AA, AG, and GG was 22.5, 52.3, and 25.2%, and for CC, CT, and TT 35.5, 51.3, and 13.2%, respectively. The A640G and the C242T polymorphisms were not associated with severity of CAD and endothelial function. The frequency distribution of the genotypes among patients with or without angiographically significant CAD did not reach statistical significance. Our study does not support a functional role for the A640G or C242T polymorphisms either in the severity of CAD or in determining endothelial function in older men.