The aim of this multicentre study was to document the nephrotoxicity associated with ifosfamide and evaluate risk factors in 148 children and young people with sarcomas who underwent investigation of renal function on one occasion each, at a median of 6 (range 1-47) months after completion of ifosfamide (median dose 62.0 (range 6.1-165.0) g/m2). Investigations included glomerular filtration rate (GFR), serum bicarbonate (HCO3) and phosphate (PO4), and renal tubular threshold for phosphate (Tmp/GFR). A clinically relevant nephrotoxicity score' was derived. GFR was < 90 ml/min/1.73 m2 in 61 of 123 evaluable patients, Tmp/GFR < 0.9-1.1 mmol/l (age-dependent) in 45/103, serum PO4 < 0.9-1.mmol/l (age-dependent) in 28/135, and serum HCO3 < 20 (< 18 in infants) mmol/l in 22/95. Of 76 fully evaluable patients: 50% had mild, 20% moderate and 8% severe nephrotoxicity. Higher total ifosfamide dose correlated significantly with greater glomerular and tubular toxicity (P < 0.01); other risk factors, including age at treatment, demonstrated no consistent significant independent effect. Chronic ifosfamide-related glomerular and proximal tubular toxicity were common in this large comprehensive study. Restriction of total ifosfamide dose to < 84 g/m2 will reduce the frequency of, but not abolish, clinically significant nephrotoxicity, whilst doses > 119 g/m2 are associated with a very high risk of severe toxicity.