Infants of diabetic mothers have an increased frequency of congenital anomalies, including CNS malformations. Fetal hyperglycemia may promote such damage via oxidative stress. Postmortem studies have shown that fetal hyperglycemia associated with maternal diabetes results in islet cell hyperplasia. Islet cell hyperplasia may correlate with the presence of oxidative stress injury in the CNS because of hyperglycemia and related metabolic derangement. This study examines 3-nitrotyrosine immunoreactivity as a marker of oxidative stress in the brains of fetuses stratified by the presence or absence of islet cell hyperplasia and CNS developmental anomalies. Fetuses with both islet cell hyperplasia and CNS developmental anomalies showed a 1.8-fold increase in semiquantitatively scored 3-nitrotyrosine immunostaining compared to negative controls. Fetuses with islet cell hyperplasia but no CNS anomalies demonstrated a 1.6-fold increase. Comparison between fetuses with islet cell hyperplasia which were stratified by presence or absence of CNS anomalies were not statistically different but did show more intense staining in those with CNS malformations. These results support the contention that hyperglycemia may contribute to CNS malformation via oxidative stress.