Objective To evaluate the effects of folic acid,vitamin B6 and B12 supplementation on plasma homocysteine level and risk of cardiovascular disease.Methods The databases,including Embase,Pubmed,Ovid,Biosis,China National Knowledge Infra-structure(CNKI),Wanfang Data,VIP Database for Chinese Technical Periodical (VIP),Chinese Biomedical Literature Database (CMB),were searched to identify random control trials between February 1994 to February 2014 on the effect of folic acid,vitamin B6 and B12 supplementation on plasma homocysteine level and risk of cardiovascular disease.The screening,data extraction and quality assessment were conducted in accordance with the inclusion and exclusion criteria by two reviewers independently.The software Review Manager 5.2 was used.Funnel plots and Egger's regression test were applied to evaluate the publication bias.Results Data from 12 studies including 34 481 patients were analyzed using a fixed-effects model.Funnel plot and Egger's test(P ＞ 0.10) confirmed the absence of publication bias.No statistically significant heterogeneity was detected on testing after excluding the sources of heterogeneity (chi-square test,I2 ＜ 50％).Baseline homocysteine levels were similar between the placebo and folic acid,vitamin B6 and B12 groups (all P ＞ 0.05).Mean homocysteine levels were significantly lower with folic acid,vitamin B6 and B12 therapy compared with placebo during follow-up (all P ＜ 0.05).The pooled relative risks with 95％ confidence intervals of outcomes for patients treated with folic acid,vitamin B6 and B12 supplementation compared with placebo were 0.98 (0.93-1.03) for cardiovascular event,0.97 (0.87-1.07) for coronary artery disease,1.00 (0.92-1.08) for myocardial infarction and 0.92(0.82-1.03) for cardiovascular death.Conclusions Folic aicd combined with vitamin B6 and B12 treatment significantly reduced plasma homocysteine level,but did not affect the risk of cardiovascular disease.Thus,folic acid combined with vitamin B6 and B12 should not be recommended as secondary prevention of cardiovascular diseases.