Background Voxel-based morphometry (VBM) has demonstrated structural brain changes between patients with Major Depressive Disorder (MDD) and healthy individuals. The initial response to antidepressants is crucial to predict prognosis in the treatment of MDD. The aim of the present study was to investigate gray matter abnormalities predicting antidepressant responsiveness and the relationships between volumetric differences and clinical/cognitive traits in MDD patients. Methods Fifty MDD patients who received 8 week period antidepressant treatment and 29 healthy controls participated in this study. VBM was applied to assess structural changes between MDD groups and control group. Neuropsychological tests were conducted on all participants. Results Both treatment responsive and non-responsive patients showed a significant volume reduction of the left insular, but only non-responsive patients had decreased volume in the right superior frontal gyrus compared to healthy controls. The comparison between treatment responsive and non-responsive patient groups demonstrated a significant difference in gray matter volume in the lingual gyrus. The larger volume of lingual gryus predicted early antidepressant response, which was attributable to better performance in neuropsychological tests. Limitation This study included a small sample size and the patients received various antidepressants and benzodiazepines. Conclusion Our findings suggest that the patients who responded poorly to antidepressants were morphologically and cognitively impaired, whereas the treatment responsive patients showed less structural changes and relatively preserved cognitive functions. The lingual gyrus may be a possible candidate region to predict antidepressant responsiveness and maintained cognition in MDD.