Many studies have indicated that depression is associated with impairment of the topological organization of the brain functional network, which may lead to disruption of mood and cognition in depressive patients. The abnormality of homotopic connectivity provides a basis for the clinical manifestations of depression, such as emotional and cognitive disorders. Several studies have investigated the abnormal imbalance of homotopic regions between the hemispheres in depressive patients. However, the reported findings are inconsistent. Additionally, the published studies have focused on only the grey matter when investigating functional connectivity abnormalities of the bilateral cerebral hemispheres in major depressive disorder (MDD). The aim of this study is to investigate functional connectivity abnormalities of the bilateral cerebral hemispheres in patients with first-episode, drug-naive MDD using a voxel-mirrored homotopic connectivity (VMHC) method. Based on DSM-IV diagnostic criteria, 23 first-episode, drug-naive MDD patients were recruited, together with 20 gender- and age-matched healthy normal controls. A Philips Achieva 3.0 T MRI scanner was used to acquire brain functional images at resting state as well as high-resolution structural images. The functional images were preprocessed by using Data Processing Assistant for Resting-State Functional MR Imaging toolkit and SPM8.VMHC between the bilateral hemispheres was computed and compared between the MDD and control groups. The correlation between the VMHC values of the abnormal homotopy function areas and the Hamilton Depression Rating Scale (HAMD) was evaluated in the MDD patients. Compared with the control group, the MDD patients showed significantly decreased VMHC values in the bilateral brain regions including the insular, putamen, and frontal white matter. The MDD patients did not exhibit increased VMHC values in any brain regions compared with the normal controls. In addition, a negative correlation was observed between the VMHC value in the frontal lobe white-matter and the HAMD in the MDD patients. Abnormalities in brain homotopic functional connectivity observed in this study may indicate abnormal neural circuits related to aberrant cognition and emotional processing in MDD. Although the physiological significance underlaying abnormal VMHC in white matter in the frontal lobe needs further research, our study new angle to investigate the role of white-matter abnormalities in MDD as well as other psychiatric disorders.