Osteosarcoma and Ewing sarcoma are the 2 most common primary malignant bone tumors in children. In control mice, metastatic tumors were found within the lungs and in various abdominal organs. We noted a statistically significant decrease in metastatic burden in mice with Ewing sarcoma treated with adjuvant DFMO (P = .045). Moreover, mice treated with neoadjuvant ifosfamide in combination with adjuvant DFMO developed far fewer metastases compared with control mice or mice treated with ifosfamide alone (P = .0005). With these promising results, we investigated the mechanism by which DFMO can prevent metastasis in both Ewing sarcoma and osteosarcoma.