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Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection associated with the reactivation of the JC virus, causing a severe demyelination within the central nervous system in patients with immunosuppression caused by disease or secondary to use of drugs. Several therapies used in the treatment of MS have reported cases of associated PML, most cases being related to Natalizumab treatment. In this article we review specific MS medication with a reported risk for PML, and also revise PML epidemiology, pathogenesis, treatment and available approaches on therapy in patients at high risk for developing this infection.