The default mode network (DMN) is a group of brain regions characterized by self-referential functions. Studies have found alterations in the structure and function of DMN regions in individuals with major depression, suggesting a basis for the disordered self-referential thought in depression. This study used fMRI to examine DMN functionality in patients with major depression during an affective reappraisal task. The results showed that depressed subjects, but not controls, failed to reduce activity in widely distributed elements of the DMN (ventromedial prefrontal cortex, prefrontal cortex, anterior cingulate, lateral parietal cortex, and lateral temporal cortex) while looking at negative pictures and reappraising them. Additionally, looking at negative pictures elicited significantly greater increases in activity in other DMN regions (amygdala, parahippocampus, and hippocampus) in depressed subjects compared to controls. These findings suggest that depression is characterized by both heightened stimulus-induced activity and a failure to normally down-regulate activity within the DMN, providing a brain network framework for understanding the pathophysiology of depression.The default mode network (DMN) is a group of brain regions characterized by self-referential functions. Studies have found alterations in the structure and function of DMN regions in individuals with major depression, suggesting a basis for the disordered self-referential thought in depression. This study used fMRI to examine DMN functionality in patients with major depression during an affective reappraisal task. The results showed that depressed subjects, but not controls, failed to reduce activity in widely distributed elements of the DMN (ventromedial prefrontal cortex, prefrontal cortex, anterior cingulate, lateral parietal cortex, and lateral temporal cortex) while looking at negative pictures and reappraising them. Additionally, looking at negative pictures elicited significantly greater increases in activity in other DMN regions (amygdala, parahippocampus, and hippocampus) in depressed subjects compared to controls. These findings suggest that depression is characterized by both heightened stimulus-induced activity and a failure to normally down-regulate activity within the DMN, providing a brain network framework for understanding the pathophysiology of depression.