To investigate characteristics and correlation of resting-state voxel-mirrored homotopic connectivity (VMHC) and cognitive function in patients experiencing the initial episode of depression. Methods: Thirty first-episode major depression (MD) patients and 30 normal controls (NC) were enrolled in this study. All subjects underwent resting-state fMRI (rs-fMRI), and the digit symbol test (DST), digit span test (DSPT), and verbal fluency test (VFT) were performed. Routine preprocessing of rs-fMRI data was completed. The rs-fMRI data were analyzed using VMHC. The VMHC values and cognitive function scores of the two groups were compared, and the correlation between the VMHC value and cognitive function scores was analyzed. Results: Compared with the NC group, the MD group showed significantly decreased VMHC values in the bilateral middle frontal gyrus (MFG) and bilateral superior temporal gyrus (STG) (P<0.01, AlphaSim correction, voxel number >50). Compared with the NC group, the MD group showed decreased DST, DSPT, and VFT scores (P<0.05). In the MD group, the VMHC value of the bilateral MFG was positively correlated with the DST score (r=0.45, P=0.002), and the VMHC value of the bilateral STG was positively correlated with the DSPT score and VFT score (r=0.32, P=0.01; r=0.34, P=0.02). Conclusion: In patients with first-episode depression, the VMHC value of the bilateral MFG and STG significantly decreases and is closely related to cognitive impairment.