A case of protamine-associated hypertension in a 76-year-old Caucasian woman with chronic renal failure (CRF) undergoing hemodialysis is reported. Four dialysis runs during March 1977 are described in this report; all involved the i.v. administration of heparin sodium (2500-5000 units) during the five-hour procedures. Protamine sulfate (25-50 mg) was given i.v. at the end of each procedure to neutralize excess heparin. In three of the four dialyses, the patient became short of breath, hypertensive, and tachycardic, usually for less than 10 minutes. In the last of these runs, the patient first became hypotensive and then hypertensive, and was incontinent of urine and feces. Treatment in each case consisted of elevation of the head of the bed and oxygen administration. During the forth dialysis, no adverse reaction occurred. Possible explanations of this phenomenon are discussed, including hypersensitivity to protamine sulfate products and the action of protamine on platelets resulting in serotonin or histamine release. In dialyses where the patient became hypertensive, more protamine on platelets resulting in serotonin or histamine release. In dialyses where the patient became hypertensive, more protamine sulfate was given than was needed to neutralize the heparin. In the run where symptoms were most severe, the patient received only 2500 units of heparin but was given 50 mg protamine sulfate. It is concluded that this reaction occurred as a result of administering excess protamine sulfate, which then acted on platelets. The platelets released either histamine or serotonin, which mediated rapid changes in blood pressure, heart rate, and breathing pattern.