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Background The 5,10-methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) are attractive candidates for screening for risk of neural tube defects (NTDs).The aim of the current study was to investigate matal MTHFR and MS polymorphisms and the interaction between them and their influence on children with NTDs in the Shanxi Province of north China.Methods Fifty-one mothers who previously had children with NTDs constituted the case group and 51 age-matched mothers with children that were unaffected by any birth defects constituted the control group.All subjects were genotyped for MTHFR C677T and MS A2756G polymorphisms.SPSS 11.5 software package was used for all analyses.Results There was a significant difference for MTHFR genotype distribution for one site (C677T) between the case and control groups.The T allele frequencies were significantly higher in the case group than in the control group (55.9％ vs.35.3％,P ＜0.05).A lack of association was observed for the MS A2756G polymorphism.There was an interaction between the matal MTHFR C677T genotype and MS A2756G genotype.Conclusion Genetic interaction between MTHFR and MS genes raises the probability of neural tube defects.