BACKGROUND Previous studies using voxel-based morphometry (VBM) revealed changes in gray matter volume (GMV) of patients with depression, but the differences between patients with bipolar disorder (BD) and unipolar depression (UD) are less known. AIM To analyze the whole-brain GMV data of patients with untreated UD and BD compared with healthy controls. METHODS Fourteen patients with BD and 20 with UD were recruited from the Mental Health Center of Shantou University between August 2014 and July 2015, and 20 non-depressive controls were recruited. After routine three-plane positioning, axial T2WI scanning was performed. The connecting line between the anterior and posterior commissures was used as the scanning baseline. The scanning range extended from the cranial apex to the foramen magnum. Categorical data are presented as frequencies and were analyzed using the Fisher exact test. RESULTS There were no significant intergroup differences in gender, age, or years of education. Disease course, age at the first episode, and Hamilton depression rating scale scores were similar between patients with UD and those with BD. Compared with the non-depressive controls, patients with BD showed smaller GMVs in the right inferior temporal gyrus, left middle temporal gyrus, right middle occipital gyrus, and right superior parietal gyrus and larger GMVs in the midbrain, left superior frontal gyrus, and right cerebellum. In contrast, UD patients showed smaller GMVs than the controls in the right fusiform gyrus, left inferior occipital gyrus, left paracentral lobule, right superior and inferior temporal gyri, and the right posterior lobe of the cerebellum, and larger GMVs than the controls in the left posterior central gyrus and left middle frontal gyrus. There was no difference in GMV between patients with BD and UD. CONCLUSION Using VBM, the present study revealed that patients with UD and BD have different patterns of changes in GMV when compared with healthy controls.