Changes in the normal hormonal regulation of linear growth which lead to growth failure in children with chronic renal failure (CRF) are not well understood. Previous studies indicate that serum levels of growth hormone and IGF-I and II are normal or elevated in this population; and that serum levels of poorly defined inhibitors of IGF action are increased. Using a recently developed RIA for the 25-kD IGF-binding protein (IGF-BP25), we report significant elevations of this protein in children with CRF when compared to age- and sex-matched controls. IGF-BP25 levels correlate positively with IGF-binding activity in both populations, indicating that the RIA reflects levels of bioactive protein. Although the variation of serum IGF-BP25 with chronologic age and IGF levels are preserved in CRF, the quantitative interrelationships are disrupted. Levels of the 53-kD IGF-binding protein, an IGF-binding protein derived from the high mol wt IGF complex, were also found to be elevated in the CRF population and, unlike in the control population, did not vary with age or IGF levels. IGF-BP25 has been shown to inhibit IGF mitogenic action in vitro. Our finding of elevated levels of IGF-BP25 in children with CRF suggests that this protein may play a role in the growth retardation of pediatric chronic renal failure. The significance of the elevated IGF-BP53 levels in CRF remains uncertain.