•Consumption of a high glycemic index diet during the preconception period does not appear to increase the risk for delivering a large-for-gestational-age infant (LGA).•Consumption of a high glycemic index diet during the preconception period does not appear to appreciably strengthen the association between prepregnancy body mass index and LGA.•Consumption of a high glycemic index diet during the preconception period does not appear to influence the association between prepregnancy body mass index and LGA. Diets with a high glycemic index (GI) leading to elevated postprandial glucose levels and hyperinsulinemia during pregnancy have been inconsistently linked to an increased risk for large-for-gestational-age (LGA) births. The effects of prepregnancy dietary GI on LGA risk are, to our knowledge, unknown. We examined the association of prepregnancy dietary GI with LGA births and joint associations of GI and maternal overweight/obesity and infant sex with LGA births among 10 188 infants born without congenital anomalies from 1997 to 2011, using data from the National Birth Defects Prevention Study (NBDPS). The aim of this study was to investigate this association among infants without major congenital anomalies (controls) who participated in the NBDPS and to evaluate how prepregnancy BMI and infant sex may modify this association on the additive scale. Dietary intake was ascertained using a 58-item food frequency questionnaire. We dichotomized dietary GI into high and low categories using spline regression models. Infants with a birth weight at or above the 90th percentile for gestational age and sex, according to a U.S. population reference, were considered LGA. We used logistic regression to obtain odds ratios (ORs) and 95% confidence intervals (CIs). Of the infants, 859 (9%) had a high dietary GI (cut-point: 59), and 1244 infants (12%) were born LGA. Unadjusted analysis suggested an inverse association between high dietary GI and LGA (OR, 0.79; 95% CI, 0.62–0.99). No association was observed in multivariable models when comparing high dietary GI intake between LGA births and all other births (OR, 0.94; 95% CI, 0.74–1.20) or when excluding small-for-gestational-age (SGA) births (OR, 0.94; 95% CI, 0.73–1.19). No joint associations with maternal overweight/obesity or infant sex were observed. High prepregnancy maternal GI was not associated with LGA births independently of or jointly with other factors.