Treatment of progressive multifocal leukoencephalopathy (PML) in a patient with exogenous immunosuppression starts with discontinuation of immunosuppressive medication. The restored host immunity will clear JC virus, the cause of PML, from the brain via cell-mediated immune mechanisms. Patients with solid-organ transplants will lose the transplanted organ, however, and patients who have autoimmune disorders may experience exacerbation of their underlying disease. These factors need to be weighed against the potentially fatal nature of PML. If the patient's immunosuppression is AIDS-related, highly active antiretroviral therapy (HAART) should be initiated if it has not previously been used. If the patient is already receiving HAART, the therapy should be changed to optimize treatment, with the goals of a nondetectable HIV viral load and normalization or near normalization of the CD4 count. For non-AIDS PML patients, daily intravenous cytosine arabinoside for 5 days can be offered if the patient is not pancytopenic and can tolerate a chemotherapeutic agent. For AIDS patients with PML or failing non-AIDS patients with neurologic deterioration, cidofovir can be considered. These therapies can be offered if neurologic stabilization satisfies the quality-of-life goals for the patient. For patients intolerant of other therapies or unsuited to them, oral mirtazapine or risperidone can be considered. The safety of these agents has been established in the treatment of psychiatric disease, but their efficacy has not yet been proven. Small interfering RNA (siRNA) therapy holds the promise of specific antiviral therapy, but delivery methods, safety, and efficacy are yet to be established.