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Progressive multifocal leukoencephalopathy is a neurological infectious disease caused by the John Cunningham polyomavirus (JCV), an opportunistic agent with worldwide distribution. This disease is frequently seen in immunosuppresed patients and rarely associated with systemic lupus erythematosus. In the central nervous system PML demyelinating lesions occur in the supratentorial compartment. The authors describe a rare case of PML secondary to SLE treatment with atypical presentation restricted to the posterior fossa.