Background: The increasing incidence of radiation?induced osteosarcoma of the maxilla and mandible (RIOSM) has become a signiifcant problem that can limit long?term survival. The purpose of this study was to analyze the associa?tion of clinicopathologic characteristics with treatment outcomes and prognostic factors of patients who developed RIOSM after undergoing radiotherapy for nasopharyngeal carcinoma (NPC). Methods: We reviewed the medical records of 53,760 NPC patients admitted to Sun Yat?sen University Cancer Center during the period August 1964 to August 2012. Of these patients, 47 who developed RISOM and met inclusion criteria were included in this study. Two of these 47 patients refused treatment and were then excluded. Results: For all patients treated for NPC at Sun Yat?sen University Cancer Center during the study period, the total incidence of RIOSM after radiotherapy was 0.084% (47/53,760). Two patients (4.4%) had metastases at the diagnosis of RIOSM. Thirty?nine of the 45 (86.7%) patients underwent surgery for RIOSM; most patients (24/39; 61.5%) who under?went resection had gross clear margins, with 15 patients (38.5%) having either a gross or microscopic positive margin. All patients died. The 1?, 2?, and 3?year overall survival (OS) rates for the entire cohort of 45 patients were 53.3%, 35.6% and 13.5%, respectively. The independent prognostic factors associated with high OS rate were tumor size and treat?ment type. Conclusions: RISOM after radiotherapy for NPC is aggressive and often eludes early detection and timely inter?vention. Surgery combined with postoperative chemotherapy might be an effective treatment to improve patient survival.