Therapeutic radiation is commonly used in the treatment of squamous cell carcinoma of the oral cavity and pharynx. Despite the proven efficacy of this form of anticancer therapy, high-dose radiation treatment is invariably associated with numerous unwanted side effects. This is particularly true for bone, in which radiation treatment often leads to osteoradionecrosis. The aim of this study was to investigate if treatment with arsenic trioxide (As(2)O(3)) could enhance the antitumor effect of radiotherapy whereas minimizing the destructive effects of radiation on bone. As(2)O(3) treatment induced a dose-dependent (1-20 mumol/L) inhibition of endothelial and tumor cell (OSCC-3 and UM-SCC-74A) survival and significantly enhanced radiation-induced endothelial cell and tumor cell death. In contrast, As(2)O(3) treatment (0.5-7.5 mumol/L) induced the proliferation of osteoblasts and also protected osteoblasts against radiation-induced cell death. Furthermore, As(2)O(3) treatment was able to significantly enhance radiation-induced inhibition of endothelial cell tube formation and tumor cell colony formation. To test the effectiveness of As(2)O(3) and radiation treatment in vivo, we used a severe combined immunodeficiency mouse model that has a bone ossicle and tumor growing side by side subcutaneously. Animals treated with As(2)O(3) and radiation showed a significant inhibition of tumor growth, tumor angiogenesis, and tumor metastasis to the lungs as compared with As(2)O(3) treatment or radiation treatment alone. In contrast, As(2)O(3) treatment protected bone ossicles from radiation-induced bone loss. These results suggest a novel strategy to enhance the therapeutic efficacy of radiation treatment while protecting bone from the adverse effects of therapeutic radiation.