As stated in recent editorials,87,88 many questions remain regarding the relationship of folate, vitamin B12, and vitamin B6 to levels of homocysteine; the relationship of homocysteine to CV risk; and the best ways to demonstrate and recommend risk reduction for individual patients and for populations. The recent findings from prospective studies indicating little predictive ability of plasma homocysteine in CVD underscore the need for a more comprehensive and quantitative overview of all available data. Fortunately, a worldwide overview of observational data is now ongoing, which will provide the most reliable estimates of the strength of the relationship between plasma homocysteine levels and vascular disease (Robert Clarke, MD, written communication, October 29, 1997). Regarding the benefits of supplemental folic acid, intervention studies have clearly demonstrated that folic acid supplementation, with or without additional supplementation with pyridoxine and cyanocobalamin, reduces plasma levels of homocysteine in those with high levels45,50,67,89- 96 and in healthy subjects.97- 101 This has contributed to the enthusiasm for screening for elevated homocysteine. However, randomized trial data regarding a possible benefit of folate supplementation on CVD are nonexistent but urgently needed. Fortunately, the Women's Antioxidant Cardiovascular Study102 is testing a combination of folic acid (2.5 mg daily), pyridoxine hydrochloride (50 mg daily), and cyanocobalamin (1 mg daily) among 8171 female health professionals, aged 40 years or older, who are at high risk for CVD morbidity and mortality. Results from this and other trials of folate supplementation will provide importantly relevant information on which to base public health recommendations for reducing risks of CVD. Whether these trials will also be able to resolve whether the anticipated decreases in homocysteine are causally related to reduced risks of CVD, thereby supporting the need for screening for elevated homocysteine level, or are merely a marker of less severe disease or improved vitamin status, is less certain. Finally, if shown to be beneficial in reducing risks of CVD, folate supplementation must be an adjunct to, and not a replacement for, proscription of harmful lifestyles. Dietary enrichment with any single factor, despite its appeal and simplicity, cannot be an alternative to the somewhat more demanding, but proven, methods of reducing risks of CVD, such as avoiding cigarette smoking, lowering cholesterol levels, and controlling high blood pressure.