The symptoms associated with progressive multifocal leukoencephalopathy (PML) reflect the location of pathologic brain lesions. These symptoms include visual deficits, cognitive impairment, and motor weakness; in patients with acquired immunodeficiency syndrome (AIDS), presenting signs can also include gait disturbance, dysarthria, dysphasia, and ocular palsy. Recently, PML has been observed in patients treated with biologic agents; natalizumab recipients currently represent the second largest group of patients with PML (behind patients with AIDS). Although brain biopsy is the most accurate and reliable method for diagnosing PML, it is rarely used today. Diagnosis is usually based on detection of JC virus in the cerebrospinal fluid by polymerase chain reaction, the clinical presentation, and demonstration of PML brain lesions on magnetic resonance imaging. With immune reconstitution, the prognosis of PML has improved markedly.