Several prospective trials have shown that recombinant human growth hormone (GH) accelerates growth significantly during the first years of therapy, but the effects of long-term GH therapy with regard to long-term growth response and safety have not yet been established. Forty-five Dutch prepubertal children [28 boys, 17 girls, mean (SD) age 7.8 (3.4) years] with chronic renal insufficiency (CRI) and severe growth retardation started GH therapy between 1988 and 1991 within one of the randomized Dutch trials. Long-term GH therapy, in this study a maximum of 8 years, resulted in a sustained and significant improvement of height standard deviation score (SDS) compared with baseline values (P<0.001). The mean height SDS reached the lower end (-2 SDS) of the normal growth chart after 3 years of GH therapy. During the following years the mean height SDS gradually increased, thereby approaching the mean target height SDS after 6 years of GH therapy. Three factors were significantly associated with the height SDS after 4 years of GH therapy: height SDS at the start (+) of therapy, age at the start of therapy (-), and the duration of dialysis treatment (-). Bone maturation did not accelerate during long-term GH therapy. Children on a conservative regimen at the start of GH therapy had no accelerated deterioration of renal function during 6 years of GH therapy. The average daily GH dose administered over the years had no significant influence on the glomerular filtration rate after 4 years. GH therapy had no adverse effects or significant effect on parathyroid hormone concentration, nor were there any radiological signs of renal osteodystrophy. Puberty started at a median age, within the normal range, of 12.4 years in boys and 12.0 years in girls, respectively. Long-term GH therapy leads to a sustained improvement in height SDS in children with growth retardation secondary to CRI, resulting in a normalization of height in accordance with their target height SDS, without evidence of deleterious effects on renal function or bone maturation. A GH dosage of 4 IU/m2 per day appears efficient and safe. Our long-term data show that final height will be within the normal target height range when GH therapy is continued for many years.