Progessive multifocal leukoencephalopathy (PML) incidence has increased about fivefold due to the AIDS pandemic. The disease has an insidious onset with HIV infection as underlying illness in 85% of cases and may present with any combination of weakness, speech disturbances, limb incoordination, cognitive deficits, and visual impairment. Diagnosis is obtained by MRI with high sensitivity but low specificity revealing T2-hyperintense, small to large, sometimes confluent lesions in the white matter, sparing the subcortical U-fibers. A spinal tap can be used to diagnose PML by JC viral DNA amplification with a sensitivity of 80% and a specificity approximating 100%. Effective therapy is either cessation of immunosuppressive therapy in cancer patients or successful restoration of the immune system in HIV infection.