Hyperhomocysteinemia promotes atherosclerosis and is most commonly caused by B-vitamin deficiencies, especially folic acid, B(6), and B(12); genetic disorders; certain drugs; and renal impairment. Elevated homocysteine promotes atherosclerosis through increased oxidant stress, impaired endothelial function, and induction of thrombosis. Prospective studies have shown that elevated plasma homocysteine concentrations increase risk of cardiovascular disease by twofold and risk of cerebrovascular disease to a lesser degree. Hyperhomocysteinemia should be identified in patients with progressive or unexplained atherosclerosis and treated appropriately. Treatment of hyperhomocysteinemia is primarily through vitamin supplementation; folic acid and vitamins B(6) and B(12) are the mainstay of therapy. Betaine and 5-methyl tetrahydro-folate are also effective in lowering homocysteine levels. Treatment of moderately elevated plasma homocysteine in patients without atherosclerosis should be deferred until the completion of randomized outcome trials.