An antagonist to H1 histamine receptor and one to H2 histamine receptor were used to prevent protamine-induced hypotension in 126 Japanese patients undergoing open heart surgery. In a study comparing an H1 antagonist "diphenhydramine" and an H2 antagonist "famotidine", 103 patients were divided into four groups: 31 patients were given no drugs (Group 1), 25 patients were given 0.4 mg/kg of diphenhydramine (Group 2), 33 patients were given 0.4 mg/kg of famotidine (Group 3), and 14 patients were given both the drugs (Group 4) before protamine administration. Although the systolic arterial pressure decreased significantly after protamine administration in all groups, famotidine was found to be effective in reducing protamine-induced hypotension, whereas diphenhydramine was not effective. In order to further investigate the hemodynamic changes in a double-blinded fashion, 12 patients were given normal saline (Group 5), while 11 patients were given 0.4 mg/kg of famotidine (Group 6) before protamine administration. Again, the minimal systolic and mean arterial pressures after protamine injection were significantly higher in Group 6 than in Group 5, while left atrial pressure, central venous pressure, heart rate, and cardiac index were almost the same and remained constant in the two groups. These results strongly suggest that the H2 antagonist "famotidine" is beneficial in reducing protamine-induced hypotension after cardiopulmonary bypass, while the H1 antagonist "diphenhydramine" is not.