Background and Purpose: The association between the low emotional regulation and the brain structural change of major depressive disorder (MDD) has been proposed, but the voxel-based morphometry (VBM) studies on female MDD are rare. The purpose of the present study was to show the regional volume changes of gray matter (GM) in female patients with MDD by optimized VBM. Methods: To control subjects homogeneity, twenty female MDD patients and age, sex matched 21 normal controls were included for the VBM analysis. To identify the change of regional gray matter volume (GMV), the optimized VBM was performed with T1 MRIs. The amounts of gray/white matter and intracranial cavity volumes (ICV) were measured. The analysis of covariance (ANCOVA) and partial correlation analyses covariate with age and ICV were applied for VBM. Results: The age and ICV distributions were similar between the two groups. In the ANCOVA, the total GMV of MDD was smaller than that of normal controls. In the VBM, regional GMV was relatively decreased in the limbic system (amygdalae, ambient gyri, hippocampi heads, subiculum, posterior parahippocampal gyri, pulvinar nuclei, dorsal posterior cingulate gyri, and left pregenual cingulate gyrus). The lingual gyri, short insular gyri, right fusiform gyrus, and right inferior frontal gyrus were also showed decreased regional GMV. Conclusion: The results of this study indicate that the female MDD is mainly associated with the structural deficits of the limbic system and limbic system related cortices, which were known to the center of emotions.