OBJECTIVE - Despite interest in the effects of type 1 diabetes on the developing brain, structural brain volumes in youth with this disease have not previously been examined. This study is the first to quantify regional brain volume differences in a large sample of youth with diabetes. RESEARCH DESIGN AND METHODS - Magnetic resonance images (MRIs) were acquired from youth with diabetes (n = 108) and healthy sibling control subjects (n = 51) aged 7-17 years. History of severe hypoglycemia was assessed by parent interview and included seizure, loss of consciousness, or requiring assistance to treat. A1C values since diagnosis were obtained from medical records; median A1C was weighted by duration of disease. Voxel-based morphometry was used to determine the relationships of prior hypo- and hyperglycemia to regional grey and white matter volumes across the whole brain. RESULTS - No significant differences were found between diabetic and healthy control groups in grey or white matter. However, within the diabetic group, a history of severe hypoglycemia was associated with smaller grey matter volume in the left superior temporal region. Greater exposure to hyperglycemia was associated with smaller grey matter volume in the right cuneus and precuneus, smaller white matter volume in a right posterior parietal region, and larger grey matter volume in a right prefrontal region. CONCLUSIONS - Qualitatively different relationships were found between hypo- and hyperglycemia and regional brain volumes in youth with type 1 diabetes. Future studies should investigate whether these differences relate to cognitive function and how these regions are affected by further exposure.