Cardiopulmonary bypass generates a systemic inflammatory response including the activation of the complement cascade and leukocytes contributing to postoperative morbidity. To evaluate whether the use of heparin-coated extracorporeal circuits could reduce these activation processes, we performed a study on 30 patients undergoing coronary artery bypass grafting who were randomly perfused with a heparin-coated circuit (Duraflo II, n = 15) or with a similar noncoated circuit (control, n = 15). Standardized systemic heparinization was applied for every patient before cardiopulmonary bypass. The use of heparin-coated circuits resulted in a reduction of systemic leukocyte activation during cardiopulmonary bypass reflected by reduced elastase release (p < 0.05) and tumor necrosis factor generation (p < 0.05) manifest after release of the aortic cross-clamp. In addition, blood samples taken from both the right and left atria after reperfusion revealed that the elastase release from the pulmonary microcirculation was absent in the Duraflo II group in contrast to the control group (p < 0.05). The pattern of complement activation, likely initiating this inflammatory reaction, was modified by heparin coating in two different aspects. There was a significant reduction of C3a generation after protamine administration in patients perfused with heparin-coated circuits, and there was a decrease of complement hemolytic capacity in pooled human serum incubated with heparin-coated tubing. These observations suggest that heparin coating might bind some of the complement components from the classic pathway, thereby reducing the inflammatory response to cardiopulmonary bypass.