GH insensitivity due to GH receptor deficiency is a rare autosomal recessive condition, characterized by deletions or mutations of the GH receptor gene. Patients are refractory to both endogenous and exogenous GH, resulting in severe growth retardation. Therapy with recombinant human insulin-like growth factor-I (rhIGF-I) can bypass the defect in the GH receptor and potentially stimulate growth. We previously identified a genetically homogeneous group of patients in southern Ecuador, thus providing a patient base for a controlled clinical trial of rhIGF-I therapy. Seventeen prepubertal patients were entered in a randomized, double blind, placebo-controlled trial. Subjects received either a 12-month course of rhIGF-I (120 micrograms/kg, sc, daily) or 6 months of placebo followed by 6 months of rhIGF-I. Subjects receiving rhIGF-I showed a significant increase in growth rate, which was sustained over the 1-yr course of therapy (from 2.9 +/- 0.6 to 8.6 +/- 0.4 cm/yr). Incidents of hypoglycemia were equal in frequency in the placebo and rhIGF-I groups. One recipient of rhIGF-I developed papilledema, which resolved spontaneously. rhIGF-I therapy did not alter serum IGF-binding protein-3 concentrations. rhIGF-I treatment is effective in stimulating skeletal growth in GH receptor deficiency. Although the therapy proved to be safe, the potent metabolic actions of rhIGF-I and the persistently low levels of serum IGF carrier protein necessitate continued careful observation for side-effects.