The vermis is located in the midline of the cerebellum and is involved in the regulation of affect and cognitive processes. Although changes in vermis size have been reported in several psychiatric disorders such as schizophrenia and bipolar disorder, no volumetric studies have been conducted on samples of patients with major depressive disorder (MDD). One-hundred and five adult subjects were recruited: 35 patients who were presenting for first treatment (FT; 22 females), 35 patients with known previous treatment (PT; 22 females), and 35 healthy controls (NC; 22 females), matched for age and gender. We compared the volumes of the total vermis, the anterior lobe (V1), the superior-posterior lobe (V2), and the inferior-posterior lobe (V3), among these study groups. Anterior vermis (V1) was larger in patients with MDD with a long history of antidepressant treatment compared to healthy controls. This finding was evident only in men [F(2, 36) = 9.23, p = .001]. Patients in the FT group did not differ from healthy controls in any vermian region. We found no correlations between vermian subregional volumes and clinical variables such as illness duration or age at onset of illness. We speculate that the larger anterior vermis volumes might arise from abnormalities in connectivity or as compensatory responses to the prefrontal dysfunction noted in patients with MDD but confirmation of this hypothesis awaits further studies.