Bone scan with Tc-99m (technetium) diphosphonate is sensitive, but non-specific for musculoskeletal tumors. Tl-201 (thallium), Tc-99m-sestamibi, Tc-99m-tetrofosmin, and F-18-fluorodeoxyglucose (F-18-FDG) can visualize tumors more specifically and are therefore useful in orthopedic oncology. However, cartilaginous tumors are characterized by histological and biological features, which potentially impair specific radionuclide imaging. A case of a patient with a low-grade primary chondrosarcoma of the femur and a false negative Tl-201 scan is presented. Tc-99m-based tumor-localizing compounds (sestamibi, tetrofosmin), as well as metabolic and receptor-imaging radiopharmaceuticals have also been reported to fail in low-grade chondrosarcomas imaging. Low cellularity, mitochondrial specialization and the presence of an efflux membrane pump may contribute to poor imaging. A negative Tl-201 or Tc-99m-sestamibi scan should be interpreted with caution, when the possibility of a chondrosarcoma is not negligible.