High doses of morphine can produce significant cardiovascular effects generally attributed to histamine release. The authors examined the possibility that H1 and H2 histamine antagonists might prove beneficial in preventing these responses. In a randomized double-blind study, four groups of 10 patients each received 1 mg/kg morphine and either a placebo, diphenhydramine (H1), cimetidine (H2), or both of the histamine antagonists. The morphine-placebo group demonstrated a marked elevation in plasma histamine levels (880 +/- 163 to 7437 +/- 2684 pg/ml), a decrease in systemic vascular resistance (SVR) (15.5 to 9.0 l torr/(l . min-1) and diastolic BP (71 +/- 3 to 45 +/- 4 torr) and an increase in cardiac index (CI) (2.4 +/- 0.2 to 3.0 +/- 0.21 . min-1 . m-2). The administration of either cimetidine or diphenhydramine with morphine provided minimal protection. Those patients who received morphine and both antagonists demonstrated significant attenuation of these responses (CI 2.5 +/- 0.2 to 2.5 +/- 0.1 l . min-1 . m-2; SVR 17.4 to 14.6 torr/(l . min-1) although plasma histamine levels showed a comparable increase (1059 +/- 222 to 7653 +/- 4242 pg/ml). These data demonstrate directly that many of the hemodynamic effects of morphine can be attributed to histamine release. They further demonstrate that significant hemodynamic protection can be obtained by the use of histamine antagonists and the combination of H1 and H2 antagonists is superior to either given alone.