Down syndrome (DS) is a complex genetic and metabolic disorder attributed to the presence of three copies of chromosome 21. The extra chromosome derives from the mother in 93% of cases and is due to abnormal chromosome segregation during meiosis (nondisjunction). Except for advanced age at conception, maternal risk factors for meiotic nondisjunction are not well established. A recent preliminary study suggested that abnormal folate metabolism and the 677 (C->T) mutation in the methylene-tetrahydrofolate reductase (MTHFR) gene may be maternal risk factors for DS. Frequency of the MTHFR 677 (C->T) and 1298 (A->C) mutations was evaluated in 36 mothers of children with DS and in 200 controls. The results are consistent with the observation that the MTHFR 677 (C->T) and 1298 (A->C) mutations are more prevalent among mothers of children with DS than controls. In addition, the most prevalent genotype was the combination of both mutations. The results suggest that mutations in the MTHFR gene are associated with maternal risk for DS