BACKGROUND: The white matter (WM) of patients who suffer from depression after long-term coronavirus disease 2019 (COVID-19) showed a dynamic change. However, to date, no research on the dynamic change in the WM of patients who develop severe depression after multiple COVID-19 infections has been conducted. This study aimed to evaluate long-term WM changes in patients who experience mild or moderate depression after their first COVID-19 infection followed by severe depression after their second infection. METHODS: In total, 27 outpatients who developed severe depression after two COVID-19 infections (the patient group) and 28 outpatients who developed mild or moderate depression after one COVID-19 infection (the control group) were included in this prospective study. Psychological assessments for depression, anxiety, and insomnia were conducted 3-6 months after infection. Diffusion tensor imaging was performed. The fractional anisotropy (FA), mean diffusivity, axial diffusivity, and radial diffusivity were calculated and compared between the groups. The correlations between the psychological scores and image parameters were analyzed. RESULTS: There was no difference between the two groups in terms of age (51.857±2.770 CONCLUSIONS: The present study revealed impairments in the WM integrity of patients who developed severe depression within 3-6 months of repeated COVID-19 infections. The findings revealed the mechanism of COVID-19-related depression and underscored the importance of psychological intervention after COVID-19 infection.