We investigated the treatment effects of aripiprazole monotherapy in first-episode medication-naïve patients with major depressive disorder (MDD). The accompanying changes in the gray matter volume (GMV) were also explored.Fifteen patients completed the trial and received structural scans by 3-Tesla magnetic resonance imaging at baseline and partially responding state (sixth week). To account for the test-retest bias, 27 healthy controls were scanned twice within 6 weeks. We utilized optimized voxel-based morphometry with different comparisons between groups.The partially responding patients with MDD had greater GMV in left middle frontal gyrus and left superior parietal gyrus when compared with baseline. However, they had decreases in the GMV of right orbitofrontal gyrus and right inferior temporal gyrus after response. The partially responding patients with MDD still had residual GMV deficits in right superior frontal gyrus when compared with controls. However, the lack of second patient group without aripiprazole intervention would be a significant limitation to interpret the aripiprazole-specific effects on GMV.The changes in the GMV of fronto-parieto-temporal regions and residual GMV deficits in the superior frontal gyrus might represent "state-dependent brain changes" and "residual-deficit brain regions," respectively, for aripiprzole monotherapy in MDD.