Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the central nervous system (CNS) caused by the JC (John Cunningham) virus. This virus is common and generally innocuous in an immunocompetent host, but in immunocompromised individuals, the JC virus causes CNS demyelination that is usually irreversible and fatal. The incidence and reported deaths due to PML increased significantly with the onset of the AIDS epidemic. Also, PML has been reported in the setting of iatrogenically induced immunosuppression, most recently in 3 patients with psoriasis treated with efalizumab. While PML is rare, it must be considered in any immunosuppressed patient presenting with neurologic deficits. Dermatologists using immunosuppressant agents should have a very low threshold to involve neurologists in the care of these patients.