Radiation-induced osteosarcoma is a rare complication after irradiation of primary malignancies. In the chest wall, it is usually secondary to radiotherapy for breast cancer or lymphoma. We report a rare case of radiation-induced osteosarcoma of the sternum after mediastinal irradiation of a thymoma. A 49-year-old woman presented with a sternal tumor 17 years after surgery plus mediastinal irradiation (50 Gy) for a stage III thymoma. On biopsy, this second tumor was diagnosed as a radiation-induced osteosarcoma. Systemic survey revealed additional metastatic spread to vertebrae and pelvis. Despite intensive combination chemotherapy that initially stabilized her disease, the patient died 2 years after the diagnosis was made. Because thymoma patients receiving mediastinal irradiation are thus at additional risk of radiation-induced secondary malignancy, long-term follow-up is advisable.