We conclude that DKI-derived WMTI metrics may be a valuable tool in assessing the WM changes of medically complex HIV-infected individuals. While not powered to examine potential etiologies of WM changes in this pilot sample, regional variations in WMTI metrics were seen. When contrasted with changes consequent to chronic MS of similar duration, HIV and its comorbidities appear to result in similar degrees of axonal damage, but regionally variable amounts of myelin loss and extraxonal abnormality.