Peak width of skeletonized mean diffusivity (PSMD) effectively reflects the mean diffusivity distribution across the white matter and is considered a novel biomarker for cerebral small vessel disease (CSVD). Neurofilament light chain (NFL) is observed to be released in neurodegenerative diseases with large myelinated axonal degeneration. In our research, we explored the relationship of PSMD with NFL levels in non-dementia adults. In the Alzheimer's Disease Neuroimaging Initiative, after adjusting for potential confounders, we used linear regression models to study the relationship of PSMD with plasma NFL levels in the total population and different white matter brain regions. Additionally, we analyzed the relationships in subgroups. Furthermore, we used a linear mixed effects model to assess the long-term effect of baseline PSMD on longitudinal changes in plasma NFL levels. The results showed that PSMD was correlated with elevated plasma NFL levels in the total population, with significant associations observed in late-life, APOE4 non-carriers, and A- (amyloid-negative) subgroups. Further analysis of different white matter brain regions revealed a correlation in the body of the corpus callosum, superior corona radiata, posterior thalamic radiation, sagittal stratum, fornix/stria terminalis, and superior fronto-occipital fasciculus. Moreover, individuals with higher PSMD demonstrated a faster increase in plasma NFL levels in the total population, which was significant in the late-life and A- subgroups. This study demonstrated that PSMD was associated with plasma NFL, suggesting that CSVD was related to neurodegenerative disorders, particularly in the body of the corpus callosum, superior corona radiata, posterior thalamic radiation, sagittal stratum, fornix/stria terminalis, and superior fronto-occipital fasciculus. At the same time, PSMD would exacerbate the damage to plasma NFL levels. These findings support the idea that plasma NFL may be a promising biomarker for CSVD.© 2025 International Society for Neurochemistry.