Progressive multifocal leukoencephalopathy is a severe demyelinating disease of the central nervous system caused by a JC papovavirus infection. Prognosis is poor with fatal outcome within 1 year in 90% of patients. Our case report shows that diffusion tensor imaging can give early and specific information about disease status and extent in a 15-year-old girl with progressive multifocal leukoencephalopathy associated with congenital human immunodeficiency virus (HIV) infection.