Progressive multifocal leukoencephalopathy. Progressive multifocal leukoencephalopathy (PML) is a lethal central nervous system (CNS) demyelinating disease caused by the human polyomavirus JC. Primary infection is asymptomatic and occurs in late childhood. JC virus persists in a latent state in different organs, notably kidney. Immunosuppression (including persons with HIV infection, receiving therapeutic immunomodulatory monoclonal antibodies to treat conditions such as multiple sclerosis, and transplant recipients) plays a key role in the viral reactivation leading to PML but also to other more recently described CNS complications. Clinical presentation depends on the localization of the lesions. Diagnosis is based on magnetic resonance imaging, the identification of JC virus in the cerebrospinal fluid, and when necessary on brain pathology. PML natural evolution is lethal. As no specific treatment with clinically relevant efficacy is available, the treatment goal is to restore host immune response to JC virus.