The role of susceptibility genes in the etiology of birth defects is unclear, but may involve in some cases multiple alleles at multiple loci. We suggest a simple epidemiologic approach to explore gene-gene interactions, and use it to reevaluate data from a recent case-control study on the possible association of neural tube defects (NTDs) with specific mutations of two genes, 5,10-methylene-tetrahydrofolate reductase (MTHFR) and cystathionine-beta synthase (CBS). We found that, compared with the common genotype, homozygosity for the MTHFR mutation alone was associated with a two-fold increased risk for NTDs, while homozygosity for the CBS mutation alone was not a risk factor. However, homozygous individuals for the mutations at both loci had a five-fold greater risk for NTDs than those with the reference genotype. Though the original study was too small to detect statistically significant differences among most of the risk estimates, these results, if confirmed by independent and larger studies, suggest that gene-gene interaction may play a role in modulating the susceptibility to NTDs in a proportion of affected individuals. This approach, moreover, could be a valuable adjunct to the study of gene gene interactions in the etiology of human disease.