Growing evidence suggests that elevated total plasma homocysteine (tHCY) levels are associated with cardiac allograft vasculopathy following heart transplantation. To assess the effect of folic acid supplementation on tHCY levels, we performed a prospective study in a cohort of 69 patients (7.0 +/- 3.2 years after heart transplantation; mean age, 55.0 +/- 9.6 years; 61 male) treated with 5 mg folic acid/day (n = 34) vs no medication (n = 35). Therapy with folic acid resulted in significantly decreased tHCY levels, from 22.6 +/- 9.6 micromol/liter to 17.3 +/- 5.5 micromol/liter (p = 0.001) within 3 months, whereas values in the control group remained unchanged. We conclude that folic acid supplementation (5 mg per day) provides a simple and effective measure to lower elevated tHCY levels in heart transplant recipients.