Cardiopulmonary bypass (CPB) precipitates inflammation that causes marked pulmonary dysfunction. Leukocyte filtration has been proposed to reduce these deleterious effects. Other studies show an improvement with aprotinin. We proposed that a combination of these two therapies would synergistically improve pulmonary outcomes. Two hundred and twenty-five patients participated in a randomized prospective study comparing pulmonary microvascular function and pulmonary shunt fraction postcoronary artery bypass grafting (CABG). The study group underwent leukocyte depletion with aprotinin during the procedure. Pulmonary microvascular function was assessed by pulmonary microvascular pressure (PMVP), a measure of pulmonary capillary edema, and pulmonary function was evaluated by comparing pulmonary shunt fractions. Elevated PMVP and increased pulmonary shunting compromise pulmonary performance. The leukocyte-depleted group had significantly reduced PMVP and pulmonary shunt fraction for at least the first 24 hours postbypass. The combination of strategic leukocyte filtration and aprotinin therapy can effectively reduce postoperative decline in pulmonary function. Cardiopulmonary bypass precipitates a variety of inflammatory effects that can cause marked pulmonary dysfunction to the point of respiratory failure, necessitating prolonged mechanical ventilation. Leukocyte filtration has been investigated previously and appears to be beneficial in improving pulmonary outcome by preventing direct neutrophil-induced inflammatory injury. Recent studies of leukocyte reduction profiles suggest that leukoreduction via leukofiltration is short lived with filter saturation occurring 30-45 minutes after onset of filtration. This phenomenon may explain the limited utility observed with higher risk patients. These patients typically require longer pump runs, so leukocyte reduction capability is suboptimal at the time of pulmonary vascular reperfusion. To more effectively protect the lung from reperfusion injury, leukocyte filtration can be delayed so that reduction of activated neutrophils is maximal at the time of pulmonary vascular reperfusion. It is, thus, conceivable that a timely use of arterial line leukoreducing filters may improve, more substantially, pulmonary function postbypass. Two hundred and twenty-five isolated coronary revascularization patients participated in this prospective, randomized trial. The patients received moderately hypothermic CBP alone (control group: n = 110) or combined with leukocyte depletion, initiated 30 minutes before crossclamp release, with filters placed in the bypass circuit (study group: n = 115). All patients also received full Hammersmith aprotinin dosing during the operation. Pulmonary microvascular pressures were lower in the study group at three hours postbypass, and continued to fall until 24 hours postbypass. In contrast, the control group measured a rise in PMVP and a continued plateau throughout 24 hours postbypass (p < 0.028). The calculated pulmonary shunt fraction also was reduced significantly throughout the study interval, with the greatest reduction occurring approximately three to six hours post-CPB (p < 0.002). Shunt fractions eventually converged at 24 hours postbypass. Outcome measures included hospital charges and length of stay, which were also markedly reduced in the treatment group. Increasing PMVPs are a direct reflection of pulmonary capillary edema, which, in conjunction with increased pulmonary shunt ratio, lead to an overall worsening of pulmonary function. Intraoperative strategic leukocyte filtration combined with aprotinin treatment improves post-CPB lung performance by reducing significantly the reperfusion inflammatory response and its sequelae. These benefits are manifested by reductions in ventilator times, hospital stay and patient morbidity.