The inheritance of most forms of epilepsy is usually considered to be multifactorial, although a number of single gene causes are known. Most previous studies of epilepsy genetics have implicated ion channel genes or ligand receptors. In a previous study of children with adverse effects of prenatal exposure to antiepileptic drugs, we noted an increased frequency of the methylene tetrahydrofolate reductase (MTHFR) 677C>T polymorphism in the mothers. To investigate this further, a new cohort of women with epilepsy has been identified from maternity hospital records and genotyped for polymorphisms in MTHFR, serine hydroxymethyl transferase (SHMT1), methionine synthase (MTR) and methionine synthase reductase (MTRR). Healthy blood donors were genotyped as controls. The frequency of the MTHFR 677TT genotype was significantly higher in women with idiopathic generalised epilepsy than in healthy controls (p=0.012, OR 2.26, 95%CI 1.13-4.51). No association was detected for the other polymorphisms tested. The MTHFR 677C>T polymorphism may be a susceptibility factor for epilepsy, and its higher frequency in women with epilepsy may contribute to the increased risk of malformation in children of women with epilepsy.