Nitric oxide has an important biological role as endothelium-derived relaxing factor, a key agent in the maintenance of normal vascular tone. It can also suppress lipoprotein oxidation, a potential anti-atherogenic property. However, in arteries subject to hypercholesterolemia or atherosclerosis, whereas nitric oxide synthesis is normal its biological activity is attenuated. This may be caused by its inactivation in the intima by components of oxidized lipoproteins acting both directly (by reaction with nitric oxide) and indirectly (by simulation of release of nitric oxide scavengers). Thus in hypercholesterolemia the normal balance between nitric oxide availability and lipoprotein oxidation is shifted to favour a self-reinforcing cycle of nitric oxide depletion and accelerated lipoprotein oxidation that may ultimately lead to atherosclerosis.