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Background Longitudinal extensive transverse myelitis (LETM) is a rare condition characterized by spinal cord lesions spanning three or more vertebral segments on T2-weighted MRI. Neuromyelitis optica spectrum disorder (NMOSD) is the most common cause, but differential diagnosis with other aetiologies, including multiple sclerosis (MS), is critical for targeted treatment.Case Series The paper reports three cases of LETM presenting in Sydney, Australia. Case 1 involved MS with central T2 hyperintensities and progressive sensory and motor decline, treated with rituximab. Case 2, also secondary to MS, displayed extensive cervical myelopathy, necessitating IV steroids and rituximab. Case 3 was diagnosed as NMOSD, due to AQP4 and GQ1B positivity, complicated by paraplegia and dysautonomia, managed with plasmapheresis, rituximab, and immunosuppressants. Functional outcomes varied, with two patients requiring assisted transfers.Discussion Differentiating NMOSD from other LETM causes requires clinical, radiological, and serological correlation. Accurate diagnosis impacts prognosis and therapeutic approaches, which range from high-dose steroids and plasmapheresis to maintenance with immunosuppressants like rituximab. Despite similar presentations, the outcomes highlight the necessity for tailored treatment based on aetiology.Conclusion LETM requires thorough evaluation to distinguish between NMOSD and other causes, such as MS, to optimize treatment and improve patient outcomes.