Progressive multifocal leukoencephalopathy is a subacute demyelinating disease that occurs in patients with defects in cell-mediated immunity, including those with AIDS and lymphoproliferative disorders. It is caused by reactivation of JC virus (JCV), which infects 70% to 90% of the population by adulthood, but remains latent in normal hosts. Once reactivated, JCV infects oligodendrocytes and astrocytes, with resultant cell lysis, leading to focal areas of demyelination and necrosis in cerebral white matter causing focal neurologic deficits and characteristic findings on MRI. Polymerase chain reaction for the detection of JCV is a sensitive and specific test, replacing brain biopsy as the initial diagnostic test in the appropriate clinical setting. Historically, the prognosis of progressive multifocal leukoencephalopathy is poor, with most patients dying within 6 months of diagnosis. Antiviral medications targeted against JCV have shown little success. However, with the use of highly active antiretroviral therapy, survival of AIDS patients with progressive multifocal leukoencephalopathy has improved.