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Introduction : Peri-operative chemotherapy is the backbone of treatment for patients with osteosarcoma. Methotrexate, cisplatinum, doxorubicin and ifosfamide are the main drugs used in chemotherapy regimens used for osteosarcoma. Areas covered : We have reviewed here the relevant literature related to the incidence and management of acute and late toxicities of systemic treatment used for the management of patients with osteosarcoma. Expert opinion : Early diagnosis and appropriate management of acute and late toxicities of chemotherapy is crucial for an efficient care of osteosarcoma patients. Although the incidence and management of chemotherapy-related acute toxicities are well known by most oncologists, the use of high doses of methotrexate have the potential to cause fatal toxicities and, therefore, needs careful monitoring. Moreover, the diagnosis of late toxicities is more challenging and requires long-term follow-up for an appropriate management.