Secondary acute leukemia (SAL) after treatment of osteosarcoma has been seldom reported in children. Two main mechanisms that can induce SAL have been described. The authors describe two patients who developed SAL after treatment with multiagent therapy. The first patient developed a secondary acute leukemia after treatment with alkylating agents and platinum compounds. The second patient had the clinical and molecular features of a secondary acute leukemia due to topoisomerase II inhibitors. The authors also discuss the data regarding cisplatin-associated SAL. Different molecular and pathogenic agents may be implicated in the development of second malignant neoplasms in long-term survivors of osteosarcomas.