A 75-year-old Asian man presented with a 3-week history of continuous pyrexia and left knee pain and swelling. He had been diagnosed with a GCTB of his left distal femur at age 35 years and was treated with bone curettage and avascular fibula grafting at that time. Postoperative radiation therapy was not performed. He remained recurrence-free for 40 years after surgery. He also had a history of fibrous dysplasia of the craniofacial bones at 35 years of age. He neither smoked cigarettes nor drank alcohol. At the initial consultation for FUO, his temperature was 38.3 °C, and a slight heat sensation and swelling were noted around his left knee. The range of motion of his left knee was restricted to 5 to 70 degrees. A patellar tap test, for fluid in the knee, was positive. Articular puncture was performed and the fluid obtained was cultured; however, no bacteria were identified. His leukocyte count was 5600/μL (4000 to 8000/μL) and C-reactive protein (CRP) was 17.8 mg/dL (<0.2 mg/dL), suggesting increased inflammatory activities. There were no other abnormalities. A plain X-ray and computed tomography (CT) showed bone grafts, including a fibula graft from the femoral metaphysis to the epiphyseal area that had been performed at the time of the initial surgery 40 years earlier. Neither bone translucency nor destruction was detected. Magnetic resonance imaging (MRI) revealed fluid retention in his medial femur and intra-articular area. T1-weighted images of the intra-osseous area showed a low to isosignal intensity, and T2-weighted images showed an isosignal to high signal intensity. There were no masses in the extra-osseous area. Bone scintigraphy revealed an abnormal accumulation in his left distal femur. Although his bacterial culture revealed no infectious organisms, based on findings including local symptoms and the inflammatory activities, surgical debridement in addition to antibiotic treatment was performed under clinical suspicion of chronic osteomyelitis of the distal femur. However, the pyrexia persisted. On histopathological examination, neither tumor osteoid formation nor residual areas of GCTB were identified, but dense proliferation of tumor cells with atypia/nuclear division was indicative of malignant transformation to undifferentiated pleomorphic sarcoma. Thus, rather than chronic osteomyelitis, a secondary malignant GCTB was diagnosed. Furthermore, the tumor specimen expressed tumor necrosis factor-α (TNF-α; Fig. ). Neoplastic fever was suspected, and a naproxen test was thus conducted. His pyrexia subsided within 24 hours of administration. There were no metastases except in his left distal femur. Under a diagnosis of a secondary malignant GCTB with neoplastic fever, his left femur was amputated. Unfortunately, a limb salvage procedure was not feasible due to widespread dissemination of malignant cells caused by the previous surgical debridement. There was no fever postoperatively, and inflammatory activities diminished markedly. To date, his course has been favorable.