Thirty-one patients with growth hormone insensitivity syndrome (GHIS) and 2 with GH gene deletion (age 11.2 (3.7-22.9) years; BA (GP) 8.2 years; height -6.5 +/- 1.6 SDS) were recruited for the multicenter study. At birth, length was more retarded (-1.38 SDS) than weight (-0.56 SDS). The rhIGF-I dose was 40-120 micrograms/kg BW twice daily s.c. In 26 patients, first year HV increased from 3.9 +/- 1.8 to 8.5 +/- 2.1 cm/year (delta (d) HT SDS 0.8 +/- 0.5). In 18 patients, second year HV was 6.4 +/- 2.2 cm/year (dHT SDS 0.4 +/- 0.5). There was normal progression of puberty. Mean progression of BA was 1.2 and 1.5 years/year during the first and second year. There was no dose effect of IGF-I on growth. Weight-for-height index (WHI) and skinfold thickness were significantly correlated at start, 12 and 24 months (r = 0.83, 0.87 and 0.79). Changes in WHI were positively correlated with dHT SDS during the first and second year (r = 0.54, 0.56). Serum IGF-I rose, IGF-II decreased, and IGFBP-3 remained constant. Adverse events were (number of occasions): headache (21) (early); hypoglycemia (13); papilloedema (1) (reversible); Bell's palsy (1) (reversible); lipohypertrophy (7) (late); tonsillectomy/adenoidectomy (3) (late). The results show that there is effective long-term treatment of GHIS with systemically administered IGF-I and support the view that IGFBPs play an important role in the action of IGF-I.