Insulin-like growth factors (IGFs) and the IGF-binding proteins (IGFBPs) appear to be important in the regulation of perinatal growth. We have shown previously that administration of epidermal growth factor (EGF) to newborn rat pups inhibits growth and decreases serum IGF-I concentrations. The experiments described here were designed to investigate the effect of EGF on the IGFBPs using ligand blots of serum and Northern analysis of hepatic RNA. EGF administration caused a rapid (within 2 h) 2-fold increase in the serum IGFBP-1 concentration. Hepatic IGFBP-1 mRNA increased even more rapidly, was increased at least 2-fold at 2 h, and remained elevated 4 h after EGF. The response to EGF was specific to IGFBP-1; IGFBP-2 hepatic mRNA content was not increased over the control value, and serum IGFBP-3 and -4 concentrations were not changed by ligand blot analysis. The IGFBP-1 response to EGF was most dramatic in the first few days of life. Although EGF lowered circulating insulin levels, EGF stimulated IGFBP-1 secretion in the presence of exogenously administered insulin. Thus, the increase in IGFBP-1 did not appear to be mediated by changes in serum insulin. These results demonstrate that EGF increases serum IGFBP-1 concentrations, probably by stimulating synthesis. The association of decreased growth and increased IGFBP-1 concentrations after EGF treatment suggests that elevated IGFBP-1 concentrations may restrict IGF bioactivity in the neonatal rat.