Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS) syndrome is a rare systemic disorder linked to plasma cell dyscrasia and is related to elevation of vascular endothelial growth factor (VEGF). Diagnosis is still challenging and pathophysiology unclear. Because VEGF drives neovascularization, we investigated skin and nerve vascularization in 6 patients with POEMS syndrome compared with 5 control groups of polyneuropathies and healthy subjects (n = 104) from the University Hospital of Limoges between 2009 and 2018. We evaluated loss of small and large fibers in these patients. Skin and nerve vascularization were quantified manually on immunofluorescence using vessel staining (anti-α-SMA antibody). Dermal vascularization was significantly higher in POEMS syndrome than in other groups, but unrelated to loss of small fibers and VEGF. Perineurial vascularization was higher in POEMS syndrome than in healthy controls, and was related to loss of large fibers and VEGF level. Our study highlights the existence of neovascularization in skin of patients with this rare disorder. These data suggest that skin neovascularization could be an additional biomarker to help in the diagnosis and understanding of POEMS syndrome. Moreover, nerve neovascularization, driven by VEGF overexpression, may play a role in the pathophysiology of large fiber loss in this condition.