Cardiac surgery with cardiopulmonary bypass (CPB) leads to a powerful activation of the hemostatic system. We assessed to what extent this activation can be attenuated by comparing three different perfusion regimens for on-pump coronary artery bypass grafting (CABG): 1) use of a closed CPB system with aspiration of blood from the operation field via the cardiotomy suction line and active venting of the heart via a roller pump; 2) use of a closed CPB system avoiding aspiration of blood from the operation field via the cardiotomy suction line, but with active venting of the heart; and 3) use of a closed system, avoidance of aspiration of blood from the operation field via the cardiotomy suction line and with passive venting of the heart into the collapsible venous reservoir. Our data show that avoidance of aspiration of blood via the cardiotomy suction line significantly reduces hemostatic activation during on-pump CABG. However, further attenuation of hemostatic activation can be achieved by further closing the system and minimizing the blood/air interface by passive venting of the heart.