BACKGROUND: Folic acid has been frequently used for hyperhomocyesteinemia in various diseases and decreases the level of homocysteine. OBJECTIVES: To assess the effect of folic acid in the level of homocysteine in epilepsy patients, and to analyze factors affecting its responsiveness and the difference of its efficacy according to methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism. METHODS: Total 75 epilepsy patients with antiepileptic drugs (AEDs) therapy were included. 41 patients had normal level of homocysteine and 34 patients with hyperhomocysteinemia (> or =12 micro mol/ ) were supplemented with folic acid for 1 year. Thirty-four patients with hyperhomocyteinemia were divided into two groups according to the responsiveness of homocysteine to folic acid; decrease group (DG) and non-decrease group (NDG). RESULTS: The level of homocysteine in patients with hyperhomocysteinemia was significantly decreased after administration of folic acid, comparing with patients with normal level. DG was younger and had more male gender, shorter duration of seizure, and initial higher homocysteine level, compared to NDG (p<0.05). Patients with mutant type of MTHFR (CT+TT) had more decreased homocysteine level after supplement of folic acid, but had more increased homocysteine level without supplement of folic acid. Comparing between MTHFR genotypes, TT type had the most decreased homocysteine level than others, but there was no significance. CONCLUSION: Folic acid is useful treatment of hyperhomocysteinemia in epilepsy patients and the supplement of folic acid might be considered in patients with mutant type of MTHFR regardless of homocysteine level. The effect of folic acid supplement is greater in younger age, male sex, shorter duration of seizure, and initial higher homocysteine level.