A case of an osteoblastoma of the proximal femur with a unique local, massive reactive periostitis mimicking osteosarcoma or osteomyelitis and unique systemic manifestiations is reported. The severe toxic manifestations included: massive weight loss, chronic fever, anemia, systemic periostosis, and other signs. Due to confusion as to diagnosis, lack of response to numerous antibiotic regimens, and severe cachexia with clinical signs of impending death, an amputation was performed. Pathologic study revealed an osteoblastoma. A thorough review of the case suggests that the signs and symptoms were possibly consequent to an immune response mounted against the tumor rather than to secondary infection, although the latter possibility cannot be completely excluded.