Diffusion studies have revealed loss of white-matter integrity in sickle cell disease (SCD), but the underlying pathophysiology is poorly understood. We combined diffusion tensor imaging with multi-parametric mapping in 23 patients and 23 controls to examine more specific imaging markers of myelin, iron, and water content. Voxel-based region of interest analyses revealed a pattern of decreased MT, R1, FA, and AD, and increased RD and MD in patients, consistent with lower myelination. Indices of lower myelination were associated with oxygen desaturation and processing speed. Our results offer insight into pathology of SCD brain changes and potential biomarkers for future trials.