High doses of morphine produced peripheral vasodilation and frequently significant hypotension. These effects are thought to be due, in part, to the release of histamine. One putative advantage of high-dose fentanyl anesthesia is its relatively small effect on peripheral vascular resistance. In a randomized study, the authors examined the possibility that the hemodynamic differences between morphine and fentanyl might be attributable to histamine release. Fifteen patients were studied prior to coronary artery bypass surgery. Subjects received in infusion of morphine (1 mg . kg-1, iv at 100 micrograms . kg-1 . min-1 [n = 8]) or fentanyl (50 micrograms . kg-1 at 5 micrograms . kg-1 . min-1 [n = 7]). Patients in the morphine group had an average 750 per cent peak increase in plasma histamine accompanied by a significant decrease in mean arterial pressure (-27 mmHg- and systemic vascular resistance (-520 dyne . s . cm-5). The greatest decrease in systemic vascular resistance occurred in those patients with the highest levels of plasma histamine (r = -0.81). Patients in the fentanyl group had no change in plasma histamine and no decrease in arterial pressure or systemic vascular resistance. Cardiac output and heart rate were comparable between the two groups. Differences in the release of histamine account for most, if not all, of the different effects of morphine and fentanyl on the peripheral vasculature.