In contrast to cross-sectional and case-control studies, which tend to report strong positive associations between plasma homocysteine and vascular risk, many prospective epidemiologic studies indicate modest associations at most, whereas other prospective studies report no evidence of association. Thus, while homocysteine may represent a causal factor in atherothrombosis, it is also possible that homocysteine is a marker of preclinical disease, or a consequence of other factors more closely linked to risk. Randomized trials are necessary to test reliably whether lowering homocysteine levels will decrease risks of atherosclerotic vascular disease. Current guidelines from the American College of Cardiology and the American Heart Association do not support population-based homocysteine screening to determine cardiovascular risk.