Although mouse models of Prader-Willi syndrome (PWS) suggest that hypoglycemia may be part of this syndrome, review of the literature shows little evidence that it is an issue in humans with PWS. Both adrenal and growth hormone deficiency can be seen in PWS, and both of these hormone deficiencies are associated with increased risk for hypoglycemia. We reviewed medical records for patients with PWS seen at the University of Florida Prader-Willi Program. Children were 2 months to 5 years of age. We recorded the presence, degree, and persistence of hypoglycemia, age of first occurrence, genetic diagnosis, and gestational age. Repeated hypoglycemia was determined if individuals had multiple blood glucose (BG) values <50 mg/dl before 1 month old, or BG levels <50 mg/dl once and additional BG values <70 mg/dl after 1 year of age. Of 95 patient charts reviewed, 12 (12.6%) had recorded hypoglycemia. Six of 12 patients with hypoglycemia had documented BG levels <40 mg/dl. Seven had their first episode of hypoglycemia within the first day of life. Of these seven individuals, five had BG <40 mg/dl. Repeated hypoglycemia was noted in 10 patients (83% of all patients with hypoglycemia). Only two with hypoglycemia had documented adrenal insufficiency. Our study suggests that infants with PWS may be predisposed to hypoglycemia from birth. Additional investigation is necessary to confirm our findings and define the cause of hypoglycemia. If the presence of hypoglycemia is confirmed, early detection and treatment may result in improved neurocognitive outcomes.