Background: Based on susceptibility-weighted imaging (SWI) visibility, deep medullary vein (DMV) scores are related to white matter damage (WMD) in patients with cerebral small vessel disease (CSVD). However, whether mechanisms are associated with DMV changes is unclear. We examined extracellular fluid (ECF) roles in white matter associations between DMV scores and white matter integrity (WMI) in patients with CSVD. Methods: We examined magnetic resonance imaging (MRI) and clinical data from 140 patients with CSVD. DMV scores (0–18) were assigned on SWI according to DMV anatomic regions and signal continuity/visibility. WMI and ECF volumes were evaluated using free water (FW) and fractional anisotropy (FA) values by diffusion tensor imaging (DTI). Results: DMV scores were independently associated with FA after adjusting for vascular risk factors, age, white matter hyperintensity (WMH) volume, and CSVD burden [\beta (95% confidence interval (CI)): –0.219 (–0.375, –0.061), p = 0.006]. We also observed a significant indirect effect of DMV scores on FA in white matter (mediated by FW in white matter) after controlling for age, vascular risk factors, WMH volume, and CSVD burden. Conclusions: DMV scores were independently related to WMI and mediated by ECF in the white matter of patients with CSVD.