Purpose: To report a case of POEMS syndrome presenting with unilateral optic disc edema and unexpectedly low systemic vascular endothelial growth factor (VEGF) levels in the setting of contralateral intravitreal (IVT) anti-VEGF therapy. Methods: A single case was reviewed. Results: A 65-year-old man with branch retinal vein occlusion in the right eye receiving IVT anti-VEGF injections presented with optic disc edema in the left eye. Systemic symptoms included skin hyperpigmentation; shortness of breath; and peripheral neuropathy characterized by numbness, tingling, swelling, and weakness of his extremities. Imaging demonstrated pachymeningeal enhancement, mixed sclerotic and lytic bone lesions, lymphadenopathy, and splenomegaly. Laboratory evaluation workup revealed a monoclonal gammopathy, and lymph node biopsy findings were consistent with the plasma cell variant of Castleman disease, supporting a diagnosis of POEMS syndrome. Notably, systemic VEGF levels were unexpectedly low (8.7 pg/mL, normal <96.2 pg/mL), likely secondary to the IVT anti-VEGF injection. Conclusions: This case highlights an atypical presentation of POEMS syndrome with unilateral disc edema and suppressed systemic VEGF levels, potentially confounded by contralateral IVT anti-VEGF treatment. Awareness of this interaction is important for accurate interpretation of VEGF levels and timely diagnosis.