In this study we explored, in man, the effect of acute attenuation of growth hormone (GH) release induced by somatostatin (SRIH) on ACTH and cortisol plasma levels. Sixteen young (8 women, aged 23–32 years, and 8 men, aged 18–27 years) and 14 elderly (8 women, aged 65–82 years, and 6 men, aged 65–70 years) healthy subjects volunteered to participate in this investigation. Each subject was tested on two separate occasions by: (1) a 90-min i.v. infusion of SRIH given in 50 ml 0.9% saline delivered at a rate of 9 µg/kg/h, and (2) a 90-min i.v. infusion of isovolumetric amounts of 0.9% saline. Plasma GH, ACTH, cortisol and glucose concentrations were determined prior and up to 180 min after SRIH or saline infusion. SRIH induced a significant (p < 0.05) decrease in plasma GH levels from basal values of 0.6 ± 0.15 and 0.5 ± 0.15 µg/l to nadir values 0.25 ± 0.1 and 0.2 ± 0.1 µg/l in young and elderly subjects, respectively. The administration of SRIH was associated with a clear-cut increase in plasma ACTH levels both in young (peak, 10.6 ± 1.6 pmol/l; AUC, 558.6 ± 147.5 pmol/l/h) and in elderly (peak, 21.3 ± 5.6 pmol/l; AUC, 841.9 ± 153.8 pmol/l/h) subjects with a significant (p < 0.01) difference as compared to saline infusion. Consistent with these results, SRIH infusion resulted in an unequivocal rise in plasma cortisol levels both in young (peak, 394.8 ± 36.4 nmol/l; AUC, 18,591.62 ± 1,372.45 nmol/l/h) and in elderly (peak, 585.6 ± 51.5 nmol/l; AUC, 24,871.05 ± 1,837.03 nmol/l/h) subjects. The ACTH and cortisol responses to SRIH were significantly (p < 0.05 and p < 0.01) higher in elderly than in young subjects. No sex-related differences occurred in the SRIH-induced activation of hypothalamic-pituitary-adrenocortical (HPA) axis. We conclude that (1) infusion of SRIH, at a dose that inhibited basal GH secretion, was associated with an activation of HPA axis, and (2) this response was higher in elderly individuals compared with younger adults. The reason for this novel and unexpected SRIH effect is presently unclear; however, the latter may be mediated, at least in part, by some central nervous system ACTH-releasing mechanisms activated by SRIH-induced decrease in GH secretion.