Children with short stature, slowed linear growth velocity, and delayed skeletal maturation may secrete growth hormone (GH) normally in response to provocative stimuli but may also have spontaneous undersecretion of GH. Orally administered clonidine, an alpha 2-adrenergic agonist, is a potent acute stimulator of growth hormone releasing hormone-mediated pituitary GH release. We performed a double-blind, placebo-controlled crossover study of nightly oral clonidine therapy (0.1 mg/m2) in 10 short, slowly growing, non-GH-deficient (stimulated GH level > 15 micrograms/L) prepubertal boys (range, 6.1 to 12.2 years; mean height standard deviation score, -2.3 +/- 0.4). Results of 6 months of clonidine therapy were compared with the results of 6 months of placebo therapy; GH responsiveness was subsequently assessed in 7 of 10 patients. Growth velocity (4.9 +/- 0.6 cm/yr baseline) was not improved by clonidine (4.6 +/- 1.2 cm/yr) or placebo (5.2 +/- 1.2 cm/yr), but it increased (p < 0.001) with GH therapy (8.2 +/- 1.3 cm/yr). Clonidine therapy similarly did not significantly affect plasma levels of insulin-like growth factor I or bone age maturation. Diminution in clonidine-stimulated peak GH levels was not observed after long-term oral clonidine therapy. Thus, in contrast to previous non-placebo-controlled studies, nightly clonidine therapy did not increase growth velocity or plasma insulin-like growth factor I levels. Subsequent acceleration in growth velocity during GH therapy suggests that a proposed increase in clonidine-induced endogenous GH secretion does not result in an effective growth-promoting stimulus.