Insulin-like growth factor I (IGF-I) has been proposed as a mediator of kidney scarring although, no interventional studies on the role of IGF-I in models of chronic kidney disease have been reported. The effect of a peptide IGF-I receptor antagonist (JB3) has been examined on kidney fibrosis and function in the rat following 5/6 subtotal nephrectomy (SNx). Male Wistar rats were anaesthetised with halothane and subjected to SNx. JB3 was delivered by subcutaneous infusion using Alzet osmotic minipumps. In vitro studies showed JB3 to displace ¹²⁵I IGF-I binding in isolated rat glomeruli and to inhibit IGF-I induced receptor phosphorylation in renal tubular cells in culture. In the 7-day SNx rat, IGF-I immunostain was present in collecting tubules and JB3 inhibited compensatory renal growth, the maximum effect occuring at 10µg/kg/day. After 90-days, the SNx rat developed proteinuria, hypertension and a fall in GFR. IGF-I immunostain was present in the tubulointerstitial space of the remnant kidney together with marked tubulointerstitial fibrosis. Treatment with JB3 10µg/kg/day had no effect on the renal fibrosis measured by Masson's trichrome staining or immunostain for collagen III & collagen IV. The proteinuria, hypertension and lower creatinine clearance all remained unchanged. The remnant kidney was associated with a 50% decrease in renal IGF-I mRNA, which was partially restored by treatment with JB3. Thus, an interventional study with an IGF-I receptor antagonist do not support a role for IGF-I in the development of renal fibrosis in the SNx rat although, IGF-I does make an important contribution to compensatory kidney growth.