The default mode network (DMN) is a brain network associated with self-referential processes. In depression, the DMN shows altered activity, which may contribute to disordered self-referential thinking. This study used fMRI to examine DMN activity in patients with major depression and healthy controls during an emotional reappraisal task. Patients with depression showed impaired regulation of DMN activity, particularly in regions such as the ventromedial prefrontal cortex, anterior cingulate, and lateral parietal cortex. During passive viewing of negative pictures, depressed individuals failed to reduce DMN activity, while control subjects did. Additionally, depressed individuals showed greater activity in DMN regions such as the amygdala, parahippocampus, and hippocampus in response to negative stimuli. These findings suggest that depression is characterized by both heightened activity in the DMN and an inability to normally down-regulate activity. The DMN is involved in emotional processing and self-referential thought, and its dysfunction may contribute to the emotional dysregulation seen in depression. The study highlights the importance of the DMN in emotional modulation and suggests that impaired DMN function may lead to difficulties in regulating emotional responses. The results provide a framework for understanding the pathophysiology of depression in terms of brain network dysfunction.The default mode network (DMN) is a brain network associated with self-referential processes. In depression, the DMN shows altered activity, which may contribute to disordered self-referential thinking. This study used fMRI to examine DMN activity in patients with major depression and healthy controls during an emotional reappraisal task. Patients with depression showed impaired regulation of DMN activity, particularly in regions such as the ventromedial prefrontal cortex, anterior cingulate, and lateral parietal cortex. During passive viewing of negative pictures, depressed individuals failed to reduce DMN activity, while control subjects did. Additionally, depressed individuals showed greater activity in DMN regions such as the amygdala, parahippocampus, and hippocampus in response to negative stimuli. These findings suggest that depression is characterized by both heightened activity in the DMN and an inability to normally down-regulate activity. The DMN is involved in emotional processing and self-referential thought, and its dysfunction may contribute to the emotional dysregulation seen in depression. The study highlights the importance of the DMN in emotional modulation and suggests that impaired DMN function may lead to difficulties in regulating emotional responses. The results provide a framework for understanding the pathophysiology of depression in terms of brain network dysfunction.