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Background: Oropouche fever, caused by the Oropouche orthobunyavirus (OROV), is an arboviral illness transmitted by midges and mosquitoes. Although commonly regarded as a mild illness, severe neurological manifestations are increasingly being reported. Case Summary: We report a 48-year-old female patient without comorbidities, from Capistrano, Ceará, Brazil, who developed Combined Central and Peripheral Demyelination (CCPD) following confirmed OROV infection. Her clinical presentation included ascending flaccid tetraparesis, bilateral facial paresis, and progressive visual loss. Neurological investigation confirmed demyelinating polyneuropathy and retrobulbar optic neuritis. Despite initial corticosteroid therapy, gradual and partial clinical improvement was observed after plasmapheresis; however, visual and motor deficits persisted even after 90 days. Conclusion: A reported case of combined central and peripheral demyelination (CCPD) associated with OROV represents an unprecedented complication, emphasizing the potential for severe outcomes linked to OROV infection. This highlights the need for increased clinical awareness and greater attention to the epidemiology of this disease. OROV infection has demonstrated the capacity to cause severe neuroinvasive complications, underscoring its critical and emerging epidemiological significance amidst the ongoing epidemic in the Americas. Driven by a novel reassortant lineage of OROV, this outbreak has been associated with previously unreported severe manifestations, including adult and fetal deaths. Enhanced surveillance systems and targeted training for the early recognition of neurological complications are essential to mitigate long-term impacts and guide public health strategies to address the growing burden of this arboviral infection.