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Background: The structural integrity of normal appearing white matter (NAWM) predicts outcomes after acute ischemic stroke (AIS); however, the underlying mechanisms are unclear. We evaluated blood-brain barrier (BBB) permeability and microstructural NAWM integrity in association with ischemic tissue outcomes.Methods: In a prospective observational study of patients with moderate to severe white matter hyperintensity (WMH) burden, 43 AIS patients had brain MRIs with dynamic susceptibilty contrast (DSC) perfusion performed within 12 hours and at 3-5 days after stroke onset. Acute infarct volume on diffusion-weighted imaging (DWIv) and final infarct volume (FIV) on follow-up FLAIR sequences were determined using a validated semi-automated method. Infarct growth (IG) was calculated from the acute DWIv subtracted from FIV. Median diffusivity metrics and BBB leakage rates (K2 coefficient) were measured in contralesional NAWM. Pearson correlation and linear regression were used for statistical analysis.Results: The K2 coefficient correlated with acute DWIv (ρ=0.30; p=0.046) and, marginally, with FIV (ρ=0.28; p=0.073). In univariate analysis, history of atrial fibrillation (β=23.8; p=0.009), and acute DWIv (β=1.2; p<0.0001) were predictive of IG. Contralesional NAWM diffusivity metrics and K2 coefficient were not predictive of infarct growth. In the multivariable model, only acute DWIv independently predicted IG.Conclusion: In a prospective study of AIS patients with moderate to severe WMH burden, BBB leakage rates correlate with acute infarct volume. These findings suggest that NAWM microvascular integrity contribute to the severity of ischemic tissue outcomes.