Although there is considerable epidemiological evidence for a relationship between plasma homocysteine and cardiovascular disease, the role of homocysteine as a causal cardiovascular risk factor remains controversial. While results from high risk population based prospective studies generally support an association of elevated homocysteine levels with increased risk of cardiovascular disease, results from low risk population based prospective studies, however, tend to indicate a weaker association, or none at all. There is not yet any proof of a cardiovascular benefit mediated by folic acid plus B vitamins supplementation; nevertheless, some recent reports focusing on intermediate endpoints support the hypothesis of a benefit. Several interventional trials are underway and the answer of whether there is a cardiovascular benefit through folic acid plus B vitamins supplementation in different populations will be available in the years to come.