Sickle cell disease (SCD) is a chronic disorder characterize by progressive cerebrovascular damage. We hypothesized that subtle cerebral injury might be visible with diffusion imaging data in these patients. Tractography based on the fiber orientation distribution function (ODF) was applied in order to investigate the character and severity of white matter injury in patients with SCD. We found both decreased and increased fiber density in patients, compared to control subjects that co-localized with silent cerebral infarctions. These data suggest progressive white matter injury and compensatory mechanisms in SCD patients.