Eight children with GH insensitivity syndrome, five with GH receptor deficiency (Laron syndrome) and three with growth-attenuating antibodies to GH, were treated with recombinant human insulin-like growth factor I (IGF-I) for 24 months (one was treated for 36 months). Their ages at the beginning of therapy ranged from 2-11 yr. The dose of IGF-I ranged between 80-120 micrograms/kg, given sc twice daily. During the first year of treatment, height velocity (HV) improved in each patient (mean pretreatment HV, 4.0 cm/yr; mean of first year, 9.3 cm/yr). HV declined by 33% during the second year (mean HV, 6.2 cm/yr). The third year HV of the one patient so treated was approximately the same as that in the second year. The mean SD score HV before therapy was -2.4 and improved to +3.8 and +0.5 after 1 and 2 yr of therapy, respectively. Increased HV was accompanied by weight gain. IGF-I-related hypoglycemia occurred infrequently and only early in treatment. No adverse changes in biochemical profile were observed. Bone age did not advance more rapidly than chronological age (mean change in bone age, 2.1 yr; mean change in chronological age, 2.2 yr). The growth of the spleen and kidneys (determined by ultrasound) was rapid in the first year of therapy. In the second year, spleen growth slowed to a normal rate in most patients. Kidney growth, however, remained relatively rapid. These results indicate that IGF-I stimulates statural growth for at least 2 yr and confirms that this peptide has the capacity to act through endocrine mechanisms. Prolonged treatment of GH insensitivity syndrome patients shows promise. The stimulation of growth by IGF-I treatment over years needs to be documented, and patients need to be monitored for side-effects.