Growth hormone (GH) secretagogues (GHS) stimulate GH secretion in vivo in humans and in animals. They act on the ghrelin receptor, expressed both in the hypothalamus and in the pituitary. It is unknown whether GHS act predominantly by increasing the release of hypothalamic GH-releasing hormone (GHRH) or by acting directly on the somatotroph cells. We studied whether a potent GHS could stimulate growth in absence of endogenous GHRH. To this end, we used GHRH knock out (GHRHKO) mice. These animals have proportionate dwarfism due to severe GH deficiency (GHD), and pituitary hypoplasia due to reduced somatotroph cell mass. We treated male GHRHKO mice for 6 weeks (from week 1 to week 7 of age) with GH-releasing peptide-2 (GHRP-2) (10 µg s.c. twice a day). Chronic treatment with GHRP-2 failed to stimulate somatotroph cell proliferation, GH secretion, and to promote longitudinal growth. GHRP-2-treated mice showed an increase in total body weight (TBW) compared with placebo-treated animals, due to worsening of the body composition alterations typical of GHD animals. These data demonstrate that GHRP-2 cannot reverse the severe GHD caused by lack of GHRH.