Background. Sixteen pediatric osteosarcoma patients, previously treated with conventional chemotherapy (including ifosfamide (IFX), 9 g/m(2)) were retreated with high-dose ifosfamide (HD-IFX, 14 g/m(2) per course), following relapse or development of a new bone tumour. The objective was to obtain responses and an improved event-free Survival (FFS). Procedure. HD-IFX was administered as described by Patel SR: J Clin Oncol 1997; 15:2378. Efficacy of treatment was assessed initially after two to four Courses. The interval between the Courses was 3 to 4 weeks. Provided a response was obtained after two to four courses, treatment was continued for an additional eight courses unless progressive disease or an untoward event, for example, renal failure occurred. Tumor sites were: lung, (10) bone (9), and bone and soft-tissue (1). Results. Response after two to four courses was 62.51%: CR 6 and PR 4. A total of 84 courses were administered to the 16 patients: (range 2-10, median 5.5 per patient). Median interval between courses was 28.5 clays (range 15-90). Five patients were disease free at 15+ to 63+ months after induction and maintenance therapy. Fever and neutropenia occurred in 12 courses. Nephrotoxicity was a major toxic event and was characterized by creatinine levels at or above three times the upper limit of normal. It was unpredictable and occurred in four patients: two were reversible. The other two patients developed full-blown renal failure; one was treated with renal dialysis, but both eventually succumbed to osteosarcoma. Our past experience also indicated that two patients treated with IFX (9 g/m(2)/course) developed renal failure: one recovered and the other required a renal transplant. Conclusions. HD-IFX is effective in patients who have failed conventional chemotherapy including IFX (9 g/m(2)). Improved disease-free survival was achieved in 30% of patients. However, renal failure constitutes an important life-threatening complication and its development is unpredictable. (C) 2004 Wiley-Liss, Inc.