Moyamoya disease (MMD) is a rare chronic vasculopathy characterized by progressive stenosis of the internal carotid arteries and the formation of fragile collateral vessels in the brain. Polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes (POEMS) syndrome is a rare paraneoplastic syndrome with a complex presentation that includes polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes. Here, we report a unique case of a 54-year-old male with MMD presenting with recurrent speech loss and mumbling, later diagnosed with POEMS syndrome. Initial imaging revealed Moyamoya vasculopathy, confirmed by computed tomographic angiography (CTA) and magnetic resonance imaging (MRI). Further examination revealed polyneuropathy, organomegaly, and elevated vascular endothelial growth factor (VEGF), meeting the diagnostic criteria for POEMS syndrome. The patient was treated with a cyclophosphamide-bortezomib-dexamethasone regimen, followed by the addition of daratumumab, resulting in clinical improvement. This case highlights the importance of thorough diagnostics and a multidisciplinary treatment approach for patients with complex comorbidities, emphasizing the need for early detection and targeted therapy in managing dual pathologies of MMD and POEMS syndrome

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