To determine the site of action of fentanyl in attenuating the pituitary-adrenal response to surgery, we have measured serum concentrations of cortisol and growth hormone during and after a standardized surgical procedure in two groups of patients. One group received fentanyl 15 micrograms kg-1 i.v. immediately before the start of surgery; a second group received fentanyl 15 micrograms kg-1 i.v. together with corticotrophin releasing factor 100 micrograms i.v., growth hormone releasing hormone 100 micrograms i.v. and arginine vasopressin 10 units i.m. The concomitant administration of the releasing factors with the opioid resulted in a significantly greater serum concentration of cortisol 30, 60, 120 and 240 min after surgery commenced, compared with the group which received fentanyl alone. Similarly, the growth hormone response in the combined group was significantly greater than in the fentanyl-alone group 30 min after the start of surgery. We conclude that the inhibitory effect of fentanyl on surgically-induced secretion of pituitary hormone was mediated directly or indirectly via the hypothalamus.