Defects of neural tube closure are among the most common of all human malformations. Epidemiological and genetic studies indicate that most of these defects are multifactorial in origin with genetic and environmental causes. Although periconceptional supplementation of the maternal diet with folic acid has been shown to reduce the recurrence and occurrence of neural tube defects (NTDs) by up to 70%, the underlying mechanism remains unknown. Folic acid enters cells of certain tissues via a receptormediated process known as potocytosis. The folate receptor alpha (FR-β£) gene codes for the protein responsible for binding folate, which is the first, and only, folate-dependent step in folate transport. The FR-β£ exons, which code for mature protein and the intron-exon boundaries, were examined for mutations in three separate studies. Initial screening was performed by singlestranded conformational polymorphism (SSCP) analysis in a subset of 1,688 samples obtained from a population-based casecontrol study of NTDs in California. In the second study, the DNA sequence of exons 5 and 6 was determined in a group of 50 NTD affected individuals. The final experiment involved using dideoxy fingerprinting (ddF) to screen a population-based case-control sample of 219 individuals who were stratified into four sub-groups on the basis of folate intake and pregnancy outcome. No polymorphism was detected in any of the four exons examined. It is unlikely that the beneficial effects of maternal folate supplementation in preventing NTDs acts through a mechanism involving pharmacological correction of a variant form of folate receptor alpha.