The mechanism of white matter (WM) microstructure alteration in major depressive disorder (MDD) is unknown. Serum neurofilament (NF) levels have been identified as promising biomarkers for axonal damage and degeneration in neurological disorders. Furthermore, elevated plasma NF levels were also reported in depressive patients with treatment resistance. The current study investigated the serum NF levels of first-episode, medication-naïve patients with different severities of MDD and assessed their relationships with WM integrity. Diffusion tensor images and serum NF levels of 82 MDD patients and 72 age- and sex-matched healthy controls (HCs) were taken. We found that serum NF levels were significantly higher in patients with MDD than those in HCs. Fractional anisotropy (FA) of six brain WM tracts (the body and genu of the corpus callosum, left superior and posterior corona radiata, and bilateral anterior corona radiata) in patients with MDD were lower than those in the HCs after family-wise error-correction for multiple comparisons. Negative correlations between serum NF levels in the severe group of MDD and the decreased FA of the left anterior corona radiata were found in MDD, which might contribute to an understanding of the pathophysiological mechanism of MDD.Copyright © 2021 Elsevier B.V. All rights reserved.