Primary cultured fibroblasts of four patients with idiopathic short stature and severe growth delay, which displayed normal growth hormone receptor expression presented a reduced ability for activation of signal transducer and activator of transcription-3 (STAT3). Impaired STAT3 activation was accompanied by cell-cycle arrest at the Go /G1 phase. Increased levels of the cyclin-dependent kinase inhibitor, p21WAF/CIPI, and reduced levels of cyclins were also detected in these patients. High concentrations of human growth hormone (1000 ng·mL−1) added to the culture medium induced activation of STAT3 and reduced the levels of p21WAF/CIPI in the fibroblasts of the four idiopathic short stature children. Treatment of these children with exogenous human growth hormone significantly augmented their growth velocity. Overall, our study provides the first evidence linking the idiopathic short stature phenotype with a functional aberration in the growth hormone signal transduction cascade which can be successfully overcome by exposure to high doses of growth hormone.