Sickle cell disease (SCD) is a devastating genetic blood disorder leading to chronic anemia and cerebral infarctions. We sought to assess microstructural properties in the WM using diffusion tensor MRI and compare them to measures of cerebrovascular reactivity (CVR). Specifically, we investigated the effect of hydroxyurea (HU) treatment in SCD. Our results show that non-HU patients had increased skew and kurtosis of mean diffusivity in the WM compared to HU patients and healthy controls, and these parameters were correlated to WM CVR in this group. This suggests HU may have beneficial effects on WM microstructural integrity in patients with SCD.