A total of 48 patients with non-metastatic osteosarcoma of the extremities were treated with a new neoadjuvant chemotherapy protocol which, prior to surgery, included the use of high dose methotrexate, cisplatin, adriamycin and ifosfamide. Cisplatin was administered intra-arterially, whereas the other drugs were given intravenously. In all of the cases response to this chemotherapy protocol was very good, allowing for conservative treatment in 46 out of 48 patients. Histological evaluation of chemotherapy response showed good (> 90%) and total necrosis in 87 and 54% of the cases, respectively. Drug toxicity was acceptable. Results were significantly better than those previously obtained in our and in other institutes when only three drugs were used (methotrexate, cisplatin, and adriamycin) in the preoperative treatment scheme. Since it has been demonstrated that grade of histological response to preoperative chemotherapy, and prognosis are closely related in osteosarcoma of the extremities treated with neoadjuvant chemotherapy, in addition to allowing for the use of conservative surgery in the majority of cases, this new protocol may also lead to a significant increase in the patient cure rate.