In this study, we examined whether leukocyte depletion from the residual heart-lung machine blood at the end of cardiopulmonary bypass (CPB) has an effect on the leukocyte counts in the systemic circulation. Twenty-six patients undergoing coronary artery bypass grafting (CABG) were randomly allocated to a leukocyte-depletion group or a control group. In the leukocyte-depletion group (n = 13), all residual blood (400 mL to 1.4 L) was filtered by leukocyte-removal filters (Pall RS01) and reinfused to the patient after CPB, whereas, in the control group, an identical amount of residual blood after bypass was reinfused without filtration (n = 13). Leukocyte-depleted allogeneic blood was transfused if needed. Preoperative risk profiles, pump support and duration of aortic crossclamping time were identical in both patient groups (ns). Leukocyte depletion removed more than 96% of leukocytes from the residual retransfused blood (p < 0.01) and significantly reduced circulating leukocytes (p < 0.05) compared with the control group. Remarkably, lower numbers of circulating leukocytes were found, not at 1 hour after reinfusion, but at 4 and 8 hours after reinfusion (p < 0.05). There were no statistical differences between the two groups with respect to postoperative blood loss, the number of transfused packed red cells and mechanical ventilation time. These results show that leukocytes can be removed from the residual blood of the heart-lung machine after CPB very effectively. Furthermore, this leukocyte depletion results in a long-term effect, the clinical significance of which has to be elucidated in ongoing studies.