Background: Alterations to microstructural integrity in white matter hyperintensities (WMH) in patients with severe leukoaraiosis are poorly understood. Neurite density and orientation dispersion imaging (NODDI) produce better estimates of myelin density than diffusion tensor MRI (DTI) and therefore may provide additional in vivo insight into WMH pathophysiology. Methods: NODDI was acquired in a prospective study of acute ischemic stroke patients with advanced white matter disease (N=36). Neurite density (ND), and orientation dispersion (OD) were calculated along with model-free diffusion parameters: mean kurtosis (MK), axial kurtosis (AK), radial kurtosis (RK), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) and fractional anisotropy (FA). Median values were measured in in the hemisphere contralateral to the incident stroke in regions of WMH and in normal appearing white matter (NAWM) and compared (paired Wilcoxon-exact test). Linear regression was performed to evaluate univariate predictors of log-transformed WMH volumes (log WMHv). Results: Patient characteristics were: mean±SD age 69±10 y, time-to-MRI 2.8±1.2 days, median [IQ] normalized WMHv 4.7 [2.3-9.3] and 61% men. MD, AD and RD were greater, while FA, MK, AK, RK, OD and ND were lower in WMH compared to NAWM (P<0.001, see Figure). Increased MD (P=0.004), AD (P<0.0001) and AK (P=0.01) in NAWM and decreased OD in NAWM (P=0.01) were significant predictors of increased log WMHv. Discussion: Diffusivity, kurtosis and ND and OD in acute stroke patients with moderate to severe leuokoaraiosis differed significantly between NAWM and WMH in the contralateral hemisphere. Reduced neurite density is suggestive of microstructural injury. Reduced OD is typically associated with greater organization, but might also reflect restricted extracellular space diffusivity. The association of MD, AD, AK and OD in NAWM with WMH burden suggests there is ongoing risk for developing future WMH.