The regulation of energy intake is a complex process involving the integration of homeostatic signals and both internal and external sensory inputs. To better understand the neurobiology of this process and how it may be dysfunctional in obesity, this study examined activity of the brain's "default network" in reduced-obese (RO) as compared to lean individuals. The default network is a group of functionally connected brain regions thought to play an important role in internally directed cognitive activity and the interplay between external and internal sensory processing. Functional magnetic resonance imaging was performed in 24 lean and 18 RO individuals in the fasted state after 2 days of eucaloric energy intake and after 2 days of 30% overfeeding in a counterbalanced design. Scanning was performed while subjects passively viewed images of food and nonfood objects. Independent component analysis was used to identify the default network component. In the eucaloric state, greater default network activity was observed in RO compared to lean individuals in the lateral inferior parietal and posterior cingulate cortices. Activity was positively correlated with appetite. Overfeeding resulted in increased default network activity in lean but not RO individuals. These findings suggest that the function of the default network, a major contributor to intrinsic neuronal activity, is altered in obesity and/or obese-prone individuals. Future studies of the network's function and its relationship to other brain networks may improve our understanding of the mechanisms and treatment of obesity.