The issue of inter-hemispheric connectivity is an emerging new area in understanding the pathophysiology of depression. This study was designed to analyse the pattern of inter-hemispheric connectivity in patients with major depressive disorder (MDD). The resting-state functional magnetic resonance imaging (RFMRI) was acquired in all enrolled patients and controls. We used a method of voxel-mirrored homotopic connectivity (VMHC) to estimate the significant differences in inter-hemispheric connectivity between 44 patients with first-episode medication-naïve MDD and 27 normal controls. The patients and controls were matched for age and gender. The patients with first-episode medication-naïve MDD showed lower VMHC than normal controls in bilateral medial frontal cortex, anterior cingulate and cerebellar posterior lobe. The strength of inter-hemispheric connectivity VMHC value was negatively correlated with clinical severity of MDD. From the results, we suggested that decreased inter-hemispheric connectivity in the anterior sub-network of the default mode network and the cerebellar posterior lobe might represent an emerging finding in the pathophysiology for MDD.