Background: Elevated blood homocysteine is a risk factor for cardiovascular disease. A 5-μmol/L increase is associated with an ≃70% increase in relative risk of cardiovascular disease in adults. For patients with established risk factors, this risk is likely even greater. Objective: Effects of increased dietary folate and recommended intakes of vitamins B- 12 and B-6 on serum total homocysteine (tHcy) were assessed in individuals at high risk of cardiovascular disease. Design: This trial was conducted at 10 medical research centers in the United States and Canada and included 491 adults with hypertension, dyslipidemia, type 2 diabetes, or a combination thereof. Participants were randomly assigned to follow a prepared meal plan (PMP; n = 244) or a self-selected diet (SSD; n = 247) for 10 wk, which were matched for macronutrient content. The PMP was fortified to provide ± 100% of the recommended dietary allowances for 23 micronutrients, including folate. Results: Mean folate intakes at 10 wk were 601 ± 143 μg/d with the PMP and 270 ±107 μg/d with the SSD. With the PMP, serum tHcy concentrations fell from 10.8 ±5.8 to 9.3 ± 4.9 μmol/L (P < 0.0001) between weeks 0 and 10 and the change was associated with increased intakes of folate, vitamin B- 12, and vitamin B-6 and with increased serum and red blood cell folate and serum vitamin B-12 concentrations, tHcy concentrations did not change significantly with the SSD. Conclusions: The PMP resulted in increased intakes and serum concentrations of folate and vitamin B-12. These changes were associated with reduced serum tHcy concentrations in persons at high risk of cardiovascular disease.