An elevated level of plasma total homocysteine is an independent, graded and strong risk factor for cardiovascular disease, which shows a strong interactive effect with conventional risk factors. It is a predictor of cardiovascular disease events in high-risk populations, but is weakly associated with risk in healthy individuals. A common polymorphism in the MTHFR gene is a major determinant of the total homocysteine level, but is unrelated to cardiovascular disease risk in most studies. This observation is in accordance with the view that high total homocysteine itself may not be particularly deleterious, but provokes vascular occlusion under conditions predisposing to cardiovascular disease.