The circulating insulin-like growth factor (IGF) axis consists of the IGF peptides, the IGF binding proteins (IGFBPs), and the IGFBP proteases. Little is known about the IGF axis in newborns, its possible perturbations in sick neonates, and the effect of nutrition on the IGF axis of such patients. The aims of this study were to define IGF axis parameters in the sera of hospitalized newborns and to correlate these parameters with the nutritional status of the infants. Serum samples obtained from twenty four hospitalized infants in the intensive care nursery were analyzed for IGF axis parameters. Insulin-like growth factor-I and IGFBP-3 by RIA were mostly within the normal range for age and were only minimally affected by gestational age. In comparison, 8 newborn infants with congenital growth hormone deficiency had IGFBP-3 levels which were below the normal range. Two infants on ECMO had elevated levels of IGFBP-3 by RIA. Western ligand blotting (WLB) demonstrated that IGFBP-2 was the major binding protein in infant serum and the 44 kDa IGFBP-3 in critically ill neonatal serum was approximately 10% of adult serum levels. IGFBP-3 by RIA in neonatal serum averaged approximately 25% of adult serum levels. Compatible with this discrepancy, a number of sick neonates had detectable levels of IGFBP-3 proteolytic activity and higher levels of IGFBP-3 fragments compared to normal adult serum in both the protease assays and Western immunoblotting. There was no correlation between any IGF axis parameter and nutritional status. In summary, sick hospitalized neonates display mostly normal IGF and IGFBP-3 levels, which are not correlated to nutritional intake. Thus serum IGFBP-3 levels maintain their diagnostic utility for growth hormone deficiency in critically ill neonates.