CONTEXT: Results of experimental studies suggest that neuroplastic changes may occur during depressive episodes. These effects have not been confirmed in patients with depression, to our knowledge. OBJECTIVE: To examine changes in the brains of patients with major depression vs those of healthy control subjects. DESIGN: Prospective longitudinal 3-year study. SETTING: Inpatients with major depression were recruited from the Department of Psychiatry and Psychotherapy, Ludwig Maximilians University of Munich, Munich, Germany, and controls were recruited from the local community. PARTICIPANTS: The study included 38 patients with major depression and 30 healthy controls. MAIN OUTCOME MEASURES: High-resolution magnetic resonance imaging was performed at baseline and 3 years later. Voxel-based morphometric measurements were estimated from magnetic resonance images, and psychopathologic findings were assessed at baseline, weekly during the inpatient phase, and then after 1, 2, and 3 years. RESULTS: Compared with controls, patients showed significantly more decline in gray matter density of the hippocampus, anterior cingulum, left amygdala, and right dorsomedial prefrontal cortex. Patients who remitted during the 3-year period had less volume decline than nonremitted patients in the left hippocampus, left anterior cingulum, left dorsomedial prefrontal cortex, and bilaterally in the dorsolateral prefrontal cortex. CONCLUSION: This study supports findings from animal studies of neuroplastic stress-related processes that occur in the hippocampus, amygdala, dorsomedial prefrontal cortex, dorsolateral prefrontal cortex, and anterior cingulum during depressive episodes.