Growth retardation is a cardinal characteristic of Down syndrome (DS). It is most pronounced from the age of 6 months, when growth starts to become growth hormone (GH) regulated. DS children have normal serum levels of GH. GH regulates the production of insulin-like growth factors (IGFs), which act as growth hormones. Therefore, the serum IGF pattern and the levels of their receptors were studied in fetuses with trisomy 21 and in patients with DS throughout life. Serum levels of IGF were determined by radioimmunoassays for insulin-like growth factors 1 and 2 (RIA-IGF-1 and RIA-IGF-2) showing normal serum RIA-IGF-2 levels throughout life. However, serum RIA-IGF-1 did not rise during childhood and remained at a low level throughout life. Determination of serum IGF by a radioreceptor assay (RRA-IGF), which detects both IGF-1 and IGF-2 as well as enhanced activity in the fetal circulation, showed a deficit in serum RRA-IGF in fetuses with trisomy 21, but at birth and throughout life elevated serum RRA-IGF levels. In spite of this, no differences were observed in fetal brain or liver binding sites for IGF-1, IGF-2, or insulin. Since in the RRA-IGF method IGF-1, IGF-2, and a fetal form of IGF-1 cross-react, it is possible that there is a delayed maturation with incomplete switching from production of the fetal form of IGF to production of the GH-regulated IGF-1 in DS. The deficit in IGF-1-like peptides might account for the growth retardation in DS. In order to study the effect of human growth hormone (hGH) therapy in DS, 5 growth-retarded children with DS were treated with hGH for 6 months. During this period the growth velocity doubled and the serum IGF-1 levels were restored to normal. Thus, DS children respond to hGH treatment.