To characterize the macromolecular forms of somatomedin (SM) in human newborn plasma, we have studied the molecular weight distribution of endogenous SM peptides as well as the content and distribution of the acid-stable and the unsaturated SM-binding proteins (SMBP) in cord blood from 13 normal term infants. The radioreceptor assayable SM peptide content was significantly reduced in newborns compared with that in normal adults. Furthermore, 50% of the SM content of newborns circulated as part of a 50,000 mol wt complex, in contrast to adult plasma where the majority of SM peptide content is found in the 150,000 mol wt range. Unsaturated SMBP was strikingly elevated in newborns (mean +/- SRM, 2.75 +/- 1.73 U/ml) compared to adult values of 0.63 +/- 0.24. Sephacryl-200 chromatography demonstrated that the unsaturated SMBP is found in the 40,000-50,000 mol wt region in newborns, adults, and GH-deficient children, although adults appear to have a secondary peak of unsaturated SMBP in the 150,000 mol wt region. Assay of the acid-stable SMBP indicated similar levels in newborns (1.15 +/- 0.26 U/ml) and adults (1.18 +/- 0.47) and strikingly lower values in GH-deficient subjects. The molecular weight of the acid-stable SMBP of newborns, adults, and hypopituitary dwarfs appeared to be similar, measuring approximately 60,000. We conclude that despite low levels of SM peptides, human cord plasma contains normal levels of the acid-stable SMBP and elevated of the unsaturated SMBP. The role of these binding proteins in cord plasma remains uncertain, but suggests that other SM peptides may be important in fetal growth.