The prevalence of deficient plasma folate status and elevated total plasma levels of homocysteine (tHcy), have been dramatically reduced after fortification of all enriched cereal grain flour products with folic acid at 140 microg/100 g flour. Against this new background fortification, we evaluated the tHcy-lowering efficacy of pharmacological dose, folic acid-based vitamin B supplementation among stable coronary artery disease (CAD) patients. Using a 2x2 factorial design, 131 stable CAD patients (mean age 60.1 years; 29.8% women) were randomly assigned to receive a combination of folic acid 2.5 mg/d, riboflavin 5 mg/d, + B12 0.4 mg/d, or placebo, with or without vitamin B6 50 mg/d, for 12 weeks of treatment. ANCOVA adjusted for baseline fasting tHcy levels revealed only very modest (ie, approximately 1.0 micromol/L), albeit statistically significant (P<0.05), reductions in mean fasting tHcy levels afforded by the folic acid-containing treatments. Additional analyses indicated that none of the treatments provided a statistically significant reduction in the 2-hour post-methionine increase in tHcy levels, relative to placebo treatment. CAD patients exposed to cereal grain flour products fortified with folic acid who receive high-dose, folic acid-containing vitamin B regimens, experience only very modest reductions in their mean fasting plasma tHcy levels. These findings have important implications for the statistical power of clinical trials testing the hypothesis that tHcy-lowering treatment may reduce recurrent atherothrombotic event rates.