Atherosclerosis has an impact on the vasomotor reaction of coronary segments to iodinated non-ionic contrast agents. Angiographically normal coronary segments show divergent vasomotor reactions to iodixanol or iopromide according to the presence of, and distance from, a coronary atherosclerotic lesion. The mechanism responsible for the above-mentioned vasomotor effect does not seem to involve flow-mediated vasodilation or endothelial nitric oxide synthesis. On the other hand, a cyclooxygenase product may be, at least in part, responsible for the vasodilating effect of non-ionic agents on epicardial coronary arteries. These findings have potential clinical implications that are herein discussed.