The pathogenesis of growth failure in uremia is not clear. Male Sprague Dawley rats (100 g) underwent 5/6 nephrectomy. Uremic (U) rats gained less weight and length (p < 0.01) compared with sham-operated pair-fed control(C) rats over a 2 week period. Tibial epiphyseal chondrocytes were grown in 10% fetal calf serum (FCS) and then studied for 72 hr in serum free media(SFM) with various growth factors. In 10% FCS, U cells grew less well (p < 0.01) than C cells. Growth responses of U cells were reduced (p < 0.001) to insulin-like growth factor(IGF)-I at concentrations of 10, 30 and 100 ng/ml in SFM compared with C cells. However, growth of U cells was normal in response to fibroblast growth factor and transforming growth factor beta-1. Growth responses of U cells were reduced (p < 0.001) to des-IGF-I and long R3, IGF-I analogues with reduced affinity for IGF binding proteins (IGFBP). Western ligand blot of conditioned media from U cells showed decreased IGFBPs. Affinity cross-linking studies showed that IGF-I binding to the IGF-I receptor was normal in U cells. Also, IGF type I receptor mRNA (RNase protection assay) and protein (immunoblot) was normal in U cells. Tyrosine phosphorylation of insulin receptor substrate 1 was reduced in U cells. Thus growth failure in uremia is associated with specific end-organ IGF-I resistance of epiphyseal chondrocytes. This resistance is not due to increased local IGFBPs, nor to abnormal expression or binding affinity of the IGF type I receptor; but rather to abnormal signal transduction of the activated IGF type I receptor.