POEMS syndrome is a rare multisystemic disease related to monoclonal plasma cell proliferative disorder. Bone lesions in POEMS syndrome are usually sclerotic, and osteolytic lesions are uncommon. Although high-dose chemotherapy administration, followed by autologous stem cell transplantation (auto-SCT) is widely indicated for POEMS syndrome, the pathogenesis and treatment strategy in patients with osteolytic lesions are still unclear. In this report, we present the rare case of a patient with POEMS syndrome with a large osteolytic lesion who was successfully treated with auto-SCT. A 36-year-old man presenting with edema and difficulty in walking was diagnosed with POEMS syndrome based on peripheral polyneuropathy, hepatosplenomegaly, elevated levels of serum VEGF, and IgA-λ monoclonal protein gammopathy. FDG-PET/CT showed high FDG avidity on a large osteolytic lesion on the right pelvic bone, in addition to multiple osteosclerotic lesions. The patient was administered immunomodulatory drugs and a proteasome inhibitor, and subsequently underwent high-dose chemotherapy, followed by auto-SCT. Post transplantation, his symptoms improved gradually, and FDG avidity on the osteolytic lesion decreased. POEMS syndrome with osteolytic lesions indicates a large tumor burden and could be a more progressive disease. For long-term disease remission of POEMS syndrome with osteolytic lesions, an FDG-PET/CT-guided decision for treatment is necessary.