Both maternal diabetes and obesity have been associated with an increased risk of neural tube defects (NTD), possibly due to a sustained state of hyperglycemia and/or hyperinsulinemia. Data were collected in the Boston University Slone Birth Defects Study (a case-control study) from 1988 to 1998. The authors examined whether high dietary glycemic index (DGI) and high dietary glycemic load (DGL) increased the risk of NTDs in nondiabetic women. Mothers of NTD cases and nonmalformed controls were interviewed in person within 6 months after delivery about diet and other exposures. Odds ratios and 95% confidence intervals were estimated from logistic regression for high DGI (> or =60) and high DGL (> or =205), with cutpoints determined by cubic spline. Of 698 case mothers, 25% had high DGI and 4% had high DGL. Of 696 control mothers, 15% had high DGI and 2% had high DGL. After adjustment for sociodemographic factors and other dietary factors, the odds ratio for high DGI was 1.5 (95% confidence interval: 1.1, 2.0); for high DGL, it was 1.8 (95% confidence interval: 0.8, 4.0). Diets with proportionally high DGI or DGL may put the developing fetus at risk of an NTD, adding further evidence that hyperglycemia lies within the pathogenic pathway.