A 39-year-old male presented with pedal edema, pleural effusion, splenomegaly, and generalized lymphadenopathy. Serum protein electrophoresis demonstrated the presence of a monoclonal protein. Histological examination of the spleen following splenectomy showed multifocal vascular proliferation and angiovascular lesions consistent with multicentric Castleman disease. He was treated with steroids and rituximab, but without improvement. The patient was found to have portal venous thrombosis and lower extremity arterial thrombosis. He then received combination chemotherapy with cyclophosphamide and mitoxantrone but developed a severe inflammatory polyneuropathy that left him disabled and wheelchair-bound. A diagnosis of multicentric Castleman disease with POEMS syndrome was made, and he then received high-dose chemotherapy with melphalan followed by autologous peripheral blood stem-cell transplantation. Following transplantation, his nerve conduction studies improved and his serum protein electrophoresis normalized. He is currently ambulatory and does not need wheelchair assistance. Hematopoietic stem-cell transplantation may be a treatment option for patients with multicentric Castleman disease and POEMS syndrome.