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Objective The aim of this study was to investigate possible associations between MTHFR polymorphism and seizure control of epileptic patients with hyperhomocysteinaemia. Methods A total of 81 epileptic patients with hyperhomocysteinaemia treated with oxcarbazepine monotherapy were enrolled in this study. All patients were offered vitamin B supplementation (2.5 mg/d folate and 1.5 mg/d mecobalamine) for six months. MTHFR C677T and A1298C polymorphisms, serum homocysteine, folate and vitamin B12 levels as well as seizure frequency and score based on the Hamilton depression scale (HAMD) were evaluated at baseline and after six months of follow-up. Results Spearman correlation analysis showed that the extent of decline of seizure frequency positively correlated with a dynamic change in serum homocysteine concentration between baseline and after six months of followup (t=0.241, p=0.015 [Spearman’s coefficient]). For the MTHFR C677T polymorphism, compared to the CC genotype, the TT genotype was associated with a significant downtrend of homocysteine (19.69 vs 10.28 mmol/L, p=0.006) and uptrend of folate (6.21 vs 2.49 ng/mL; p=0.004). The decrease in homocysteine (17.94 vs 12.52 mmol/L, p=0.001) and increase of folate (5.08 vs 2.86 ng/mL; p=0.003) were significantly greater in patients with the T allele compared to those with the C allele. Also, the TT genotype (2.33 vs 1.4, p=0.056) and T allele (1.95 vs 1.38, p=0.037) were associated with a greater decrease in seizure frequency compared to the CC genotype or C allele. The A1298C polymorphism alone was not associated with elevated homocysteine or decreased folate levels at baseline, and showed little association with response to vitamin B supplementation in epileptic patients with hyperhomocysteinaemia. However, in patients with combined 677TT/1298AA or 677TT/1298AC polymorphisms, the changes in homocysteine and folate levels and seizure frequency were more obvious. Significance MTHFR C677T polymorphism was associated with seizure control in epileptic patients with hyperhomocysteinaemia; individuals with the 677TT genotype or T allele demonstrated better seizure control.