High sugar intake has been linked to fetal anomalies in the presence and absence of insulin resistance. Using dietary data collected in the Boston University Slone Epidemiology Birth Defects Study, we examined whether high dietary glycemic index (dGI) or load (dGL) increased the risk of birth defects. Non-diabetic mothers of 1,921 cases and 704 controls were interviewed within six months after delivery (1988–1998) about pregnancy events and exposures, including a 99-item food frequency questionnaire. Case groups included amniotic bands, craniosynostosis, gastroschisis, hypospadias, small intestinal defects, anorectal defects, limb reductions, omphalocele, cleft lip and/or palate, renal agenesis, and tracheoesophageal fistula. Cubic splines were used to determine cutpoints values for high dGI and dGL in relation to the risk of each birth defect. The cutpoints were used in logistic regression models to calculate odds ratios (OR) and 95% confidence intervals (CI). Control mothers in the lowest quartile of glycemic intake were more likely to be non-Hispanic White, ≥ 30 years of age, have higher family income, have a normal body mass index, and reside in Boston. Findings were null for most case groups. The anorectal defect case group was found to have elevated risks for dGL [adjusted OR: 2.35; 95%CI: 1.1, 4.9], while estimates for dGI were elevated for the amniotic band case group [adjusted OR: 3.01; 95% CI: 1.1, 8.1]. Because this is the first paper (to our knowledge) to explore dGI and dGL in relation to a spectrum of birth defects, additional studies are needed.