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In order to clarify the relationship between anergy and immunosuppressive activity in the serum, we studied 46 previously well patients before and at three, five, seven and 28 days after surgery. Delayed hypersensitivity was measured by skin testing with four common recall antigens, and serum immunosuppressive activity was determined by the ability of the patient's serum in 10% concentration to suppress by 50% or more the phytohemagglutinin (PHA) stimulation of normal human lymphocytes as compared to pooled normal serum. Prior to surgery, all patients manifested delayed hypersensitivity to one or more antigens, and no patient had immunosuppressive serum. Fifteen patients underwent minor surgery under general anesthesia and did not develop anergy or immunosuppressive serum. Thirty-one patients underwent major cardiovascular surgery. Thirteen of these patients became anergic by day 3 after operation, and 11 of the 13 developed immunosuppressive serum. Eighteen patients maintained delayed hypersensitivity after major surgery, and only three developed immunosuppressive serum. The correlation between anergy and immunosuppressive serum was highly significant (p < 0.001). There was a significant difference in the degree of suppressive activity in the serum of the anergic and reactive patient groups for each postoperative day studied until day 28, when there was recovery of delayed hypersensitivity and lack of immunosuppressive serum. The occurrence of postoperative anergy and immunosuppressive serum was not related to the patient's age, sex, number of perioperative blood transfusions or duration of anesthesia but was associated with an increase in postoperative infectious complications (p < 0.05) and in postoperative days in the hospital (p < 0.01). Pooled immunosuppressive serum from anergic patients was fractionated by ion exchange chromatography, gel filtration and preparative high voltage electrophoresis. The majority of the immunosuppressive activity could be accounted for by an electrophoretically homogenous polypeptide-containing fraction not identified in the serum of patients undergoing minor surgery or in normal individuals. We conclude that anergy occurring after major operative trauma is associated with the appearance of a circulating immunosuppressive molecular species and that these events are in turn associated with increased patient morbidity and increased length of hospitalization.