Cerebrovascular disease (CVD) is the second leading cause of death worldwide. In addition to the traditional risk factors such as hypertension, diabetes, and hyperlipidemia, nutritional folate deficiency may be an important risk factor for CVD, especially in low-income countries. Folic acid supplementation has been considered for stroke prevention, but trial results have been variable. Therefore, in general, stroke patients do not receive folic acid supplementation routinely, partly due to the lack of consensus regarding such necessity. To be metabolically active, the synthetic folic acid, which is often taken as a supplement, needs to be enzymatically converted to 5-methyltetrahydrofolate (5-MTHF) by the endogenous enzyme methylenetetrahydrofolate reductase (MTHFR). 5-MTHF promotes homocysteine catabolism while improving endothelial function and reducing superoxide generation. It has been shown that supplementation with synthetic folic acid reduced the incidence of ischemic strokes in individuals with hypertension, but the efficacy of folic acid supplementation in primary prevention of ischemic strokes was markedly reduced in the subset of hypertensive patients with mutations in the MTHFR gene. Furthermore, supplementation with synthetic folic acid may promote accumulation of unmetabolized free folic acid which may increase risk of cancer, immune suppression, and cognitive impairment, especially in patients with mutations in MTHFR. Since MTHFR genotyping is neither feasible nor cost-effective in the vast population of patients at risk of ischemic stroke, supplementation with low-dose 5-MTHF merits examination in large well-designed clinical trials.