In the Netherlands 1 of 1.000 inhibitants undergo cardiac surgery annually. To compensate blood loss these patients receive often blood transfusions, which can cause unexpected adverse reactions. Allogeneic leukocytes may play a prominent role in the development of these adverse reactions. We found in a randomized trial in cardiac valve surgery that patients receiving buffy-coat depleted (which contain 20-30% donor leukocytes) red blood cell (RBC) transfusions had dose-dependently higher hospital-mortality and postoperative infections than patients receiving leukocyte-depleted RBCs. Cost-effectiveness analysis revealed that leukodepletion of RBCs reduces the costs after cardiac valve surgery. Additional analyses revealed that plasma transfusions were associated with mortality and platelet transfusions with postoperative infections and longer ICU-stay. Patients who received more than 3 red blood cell units had significantly higher cytokine IL-6 concentrations after leukocyte-containing, buffy-coat depleted red blood cells (RBC) as compared to patients who had received similar numbers of leukocyte-depleted RBC units. Patients who developed postoperative infections and multiple-organ-dysfunction-syndrome showed, respectively, increased concentrations of cytokines IL-6 and IL-12 in the group that received leukocyte-containing RBCs. This laboratory analysis suggests that buffy-coat depleted erythrocytes may affect the development of postoperative complications by modulation of the postoperative proinflammatory response after cardiac surgery.