To explore the relationship between genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), reduced folate carrier1 (RFC-1), methionine synthase (MTR) involved in folate metabolism and the risk of offsprings of young Chinese women with Down syndrome (DS) through a case-control study, the polymorphisms of MTHFR 677C>T, MTRR 66A>G, RFC-1 80G>A, and MTR 2756A>G in 60 mothers of children with DS and 68 control mothers were investigated by PCR-RFLP. Significant differences in alle-lic frequencies were present between the cases and controls for MTHFR (Plt;0.05), but not in allelic frequencies for MTRR, RFC-1, and MTR. Homozygous MTHFR 677C>T polymorphism was more prevalent among the mothers of children with DS than among the control mothers, with an odds ratio of 3.51 (OR=3.51, 95% CI=1.30~9.46, Plt;0.05). No significant association was observed in the combined heterozygotes. In addition, the homozygous MTRR 66A>G polymorphism was independently associated with a 3.16-fold increase in estimated risk (OR=3.16, 95% CI=1.20~8.35, Plt;0.05). The increased risk of DS for homozygous RFC-1 80G>A was not associated with MTR 2756A>G. Positive interactions were found for the following genotype-pairs: MTHFR(CT+TT)/MTRR GG, MTHFR (CT+TT)/RFC-1 AA, MTHFR CC/MTR(AG+GG), MTHFR (CT+TT)/MTR AA, MTRR GG/MTR AA, and RFC-1 AA/MTRAA. In conclusion, MTHFR 677C>T and MTRR 66A>G polymorphisms are two independent risk factors for DS pregnancies in young women, but RFC-1 80G>A and MTR 2756A>G polymorphism are not independent risk factor. A role for combined genotypes in the risk of DS pregnancies cannot be excluded.