Thirty-six patients with adult-onset GH deficiency (GHD) were examined before and after 9 months of treatment with recombinant GH. The study was conducted as a double blind, placebo-controlled, 21-month trial with a cross-over design, with each treatment period lasting for 9 months. The same dose, adjusted for body surface area, was given to men (n = 21) and women (n = 15), and the effects on body composition and biochemical parameters were evaluated with respect to gender. The extent of GHD, assessed before therapy from basal GH secretion and GH release in response to provocative tests, did not differ between the two groups. The men, however, had higher serum insulin-like growth factor I concentrations than the women (mean +/- SD, 126 +/- 71 vs. 61 +/- 32 micrograms/L; P = 0.0003), less body fat, and greater lean body mass. Upon treatment, insulin-like growth factor I concentrations increased more in men than in women (by 305 +/- 136 and 198 +/- 96 micrograms/L, respectively; P = 0.02). The men lost more body fat than the women (7.4 +/- 4.1% vs. 3.3 +/- 3.8%; P = 0.002), whereas the difference in gain in lean body mass failed to reach statistical significance. Serum levels of total cholesterol, low density lipoprotein cholesterol, apolipoprotein B, and plasminogen activator inhibitor-1 decreased in the male group (P = 0.003, P = 0.03, P = 0.0009, and P = 0.01, respectively), but not in the females. Serum markers of bone formation, namely osteocalcin, procollagen type I, bone-specific alkaline phosphatase, and a marker of bone resorption, telopeptide of collagen type I, increased more markedly in men than in women. Lipoprotein(a) increased to a similar extent in the male and female groups. The data demonstrate that men and women with GHD display marked differences in their responsiveness to GH replacement therapy. These differences should be taken into consideration when optimizing the treatment of GHD patients.