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Background The prevalence of gestational diabetes mellitus (GDM) continues to rise in the face of the obesity epidemic affecting up to 14% of some ethnic populations. Studies have shown that treatment of GDM with insulin decreases serious maternal and fetal morbidity and perinatal mortality. Oral medications are preferred by patients and this could lead to increased compliance. Glyburide remains unapproved for use in GDM. Study This was a retrospective review of 124 women who were offered glyburide therapy between November 2000 and May 2005. A cohort of 101 women was included for analysis, approximately 50% Hispanic, 33% Caucasian, and 3% African American. Neonatal outcomes reviewed included birth weight, macrosomia, weight > 90%, admission to the neonatal intensive care unit, hypoglycemia, evidence of respiratory distress (RDS), and congenital anomalies. Results Eighty percent of the pregnancies were treated successfully with glyburide. There were no reported perinatal deaths. Overall cesarean section rate was 27% and there were no reports of shoulder dystocia. The macrosomia rate was 7% and 27% of the infants were large for gestational age (LGA) with a mean birth weight of 3,307 ± 490 g. Although 21% were admitted to the NICU, only 8% required IV glucose for hypoglycemia and only 8% were treated for RDS. Three congenital anomalies were noted but glyburide was initiated after 22 weeks gestation. Conclusion Although the study was a retrospective retrieval of data, the management of these patients was standardized. Fetal growth was considered in the decisions regarding titration of glyburide and this may have contributed to neonatal outcomes such as weight, shoulder dystocia, and rate of cesarean section. Given that the relative safety of glyburide has been confirmed, outcomes with glyburide are at least comparable to outcomes with insulin, and oral medications are preferred to insulin and this may increase compliance, glyburide would be another option to treat GDM and therefore improve overall fetal morbidity.