Genetically obese (C57BL/6J ob/ob) mice have significantly reduced brain weights (-14.6%) and cortical brain volumes (-7.9%) compared to lean control mice (C57BL/6J +/+). Morphometric analyses of soma cross-sectional areas of individual neurons in select brain region also reveals significant alterations in the ob/ob mouse. Neurons from 8 out of 9 brain regions, including the ventromedial hypothalamic nucleus, show significantly decreased soma cross-sectional areas in ob/ob mice compared to controls. Only lateral hypothalamic area neurons have equivalent soma cross-sectional areas for these two mouse strains. The decreased brain weight and volume coupled with the observed morphometric changes in individual neuronal soma size suggest that the ob/ob mouse brain differs considerably from that of controls. These differences may underlie some of the endocrine abnormalities seen in this genetic obesity syndrome.