Progressive multifocal leukoencephalopathy (PML) is a rare and severe demyelinating disease of the white matter in the central nervous system (CNS), and is caused by the John Cunningham virus. Most PML cases occur in immunocompromised patients, particularly those with impaired cellmediated immunity. There is no specific therapy for PML; the main therapeutic approach is restoring host adaptive immune responses. In 2005, PML was described in two multiple sclerosis (MS) patients treated with natalizumab. MS is a chronic inflammatory demyelinating disease of the CNS that has been suggested to be associated with attacks by autoreactive lymphocytes. Disease-modifying therapies have recently been shown to reduce the frequency and severity of clinical relapse, and slow the development of disability. Although freedom from disease activity has become the primary aim of the treatment of MS, these therapies increase the risk of PML. Natalizumab is a monoclonal immunoglobulin antibody directed toward a4 integrin adhesion molecules. To date, 731 natalizumab-associated PML cases (728 MS and three Crohn's disease) have been reported, including one case of PML in a Japanese patient with MS. Fingolimod is a sphingosine 1-phosphate receptor modulator that prevents the egress of lymphocytes from lymphatic tissue. There have been 15 confirmed fingolimod-associated PML cases, including four cases in Japanese MS patients. Dimethyl fumarate is the methyl ester of fumaric acid. The anti-inflammatory mechanism of dimethyl fumarate has not yet been elucidated in detail. A total of 21 cases of PML have been reported in patients receiving dimethyl fumarate, among which five were MS patients. Dimethyl fumarate-associated PML has not been documented in Japan. In the era of disease-modifying therapies for the treatment of MS, neurologists need to consider drug-induced PML in MS.