Survival of high risk neuroblastoma patients is increased with the use of dinutuximab beta (DB). This anti-ganglioside 2 antibody promotes neuroblastoma cell killing but has on-target off-tumor nervous system side effects. A patient with high-risk neuroblastoma treated with DB and cis-retinoic acid without interleukin-2 presented with severe encephalopathy. Prompt commencement of acyclovir, steroids and intravenous immunoglobulin infusions proved unsuccessful. Symptomatic improvement concurred with the initiation of high-dose steroid pulses and serial plasmapheresis sessions. Timely management of severe DB neurotoxicity as immune-based encephalomyelitis and prompt initiation of plasmapheresis, if needed, can reverse symptoms and offer long-term recovery of the patients.