Homocysteinemia is a risk factor for cardiovascular diseases. Folic acid combined with vitamins B₆ and B₁₂ is effective in lowering homocysteine levels. This randomized placebo-controlled study was designed to determine the effect of a folic acid-based supplement on secondary prevention of clinical events in non-ST-segment elevation acute coronary syndromes. The study comprised 240 patients with either unstable angina or non-ST-elevation myocardial infarction in the previous 2 weeks who were randomized to a folate group (n = 116) or a placebo group (n = 124). The folate group received 1 mg folic acid, 400 μg vitamin B₁₂, and 10 mg vitamin B₆ daily. Clinical outcomes within 6 months were assessed. The composite endpoint of death, nonfatal acute coronary syndrome, and serious re-hospitalization was significantly higher in the folate group; serious re-hospitalization alone was significantly higher in this group. Advanced age and diabetes increased susceptibility to the composite outcome. Folic acid-based supplementation is not beneficial and may even be harmful in the secondary prevention of cardiovascular events in patients with unstable angina and non-ST-elevation myocardial infarction. Further studies on the safety of such supplements are suggested. Controlled Clinical Trials Registry no. ISRCTN30249553.