In this chapter we will discuss more about the role of homocysteine in atherosclerosis and also association between serum homocysteine with extracranial carotid atherosclerosis. Carotid atherosclerosis comprises an increase in carotid intima-media (CIMT) thickening, plaque formation and carotid stenosis. Atherogenic property of homocysteine was discovered in 1969. Atherosclerosis is initiated by endothelial dysfunction. One of the causes of endothelial abnormality is homocysteine. The development of aggregates of homocysteinylated lipoproteins with microorganisms obstructs the vasa vasorum in vulnerable plaques. In one study, serum homocysteine in the highest quartile was independently associated with extracranial carotid artery stenosis ≥50%. In another study, raised serum homocysteine was also independently associated with severe extracranial carotid stenosis in both genders. In other studies, serum homocysteine was significantly associated with carotid artery stenosis in internal carotid arteries and external carotid arteries as well as the degree of stenosis. The hypertensive patients who had raised serum homocysteine were reported to have higher risk of developing asymptomatic extracranial carotid artery stenosis.