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•We present a case of NMOSD negative for anti-AQP-4 IgG that developed with reactivation of EBV in the central nervous system.•Treatment with corticosteroid and methotrexate induced EBV-related lymphoproliferative disorder (EBV-LPD).•Chronic replication of EBV may be related with NMOSD, and cautions are needed about EBV-LPD with immunosuppressive therapy.