Donor core cooling with cardiopulmonary bypass is a valid method of clinical lung preservation. However, organ ischemia with this method is still limited to short-term intervals. Since circulating leukocytes participate in postischemic injury through the release of oxygen-derived free radicals, we examined whether leukocyte depletion by mechanical filtration could extend ischemic tolerance of the lung during preservation and subsequent double lung transplantation. Bovine donor lungs were preserved by donor core cooling (10 degrees to 15 degrees C) with cardiopulmonary bypass. Donor lungs were removed, stored in 4 degrees C donor blood for 24 hours, and transplanted. Graft function was studied for 6 hours after transplantation. Group 1 animals (n = 6) underwent standard cardiopulmonary bypass with whole blood for donor and recipient procedures. In group 2 (n = 6), leukocyte filters were incorporated into the cardiopulmonary bypass circuit in both donor and recipient operations. In group 2 recipient animals leukocyte counts decreased to 3% of mean baseline values and remained low during the experiment. Postischemic lung function (assessed by systemic arterial oxygenation, pulmonary artery pressure, pulmonary vascular resistance, airway pressure, lung water content, and end-point histologic characteristics) was significantly better preserved in the animals with leukocyte depletion. Leukocyte depletion by mechanical filtration in both donor and recipient improves the ischemic tolerance of the lung beyond that provided by donor core cooling alone, resulting in excellent lung function after 24 hours of ischemia.