The authors conducted a subcortical analysis of first-episode, medication-naïve patients with major depressive disorder comorbid with panic disorder. A sample of 15 patients were compared with 15 healthy controls to explore volumetric differences of subcortical regions and hippocampus, including the putamen and thalamus. The patient group had smaller volumes of left hippocampus, thalamus, and putamen. Subcortical and hippocampal volumes in the patient group showed significant negative correlations with symptom severity. Structural alterations of the putamen, hippocampus, and thalamus might represent the structural pathophysiology of major depressive disorder comorbid with panic disorder.