BACKGROUND: Hyperacute lung dysfunction, which is always associated with pulmonary pig-to-primate xenotransplantation is not well understood. The mechanisms associated with its occurrence seem to differ from mechanisms involved in hyperacute xenograft rejection seen in porcine hearts or kidneys transplanted into primates. To determine the contribution of anti-Gal alpha1-3Gal antibodies (alphaGAb) in such a process, we performed a set of orthotopic pig lung transplants into baboons depleted of alphaGAb and compared graft function and survival with those receiving only immunosuppression. STUDY DESIGN: Pigs expressing human membrane cofactor protein served as donors. All baboons received triple immunosuppressive therapy. Depletion of alphaGAb in the experimental group (n = 4) was done by way of immunoadsorption using immunoaffinity membranes. Controls (n = 4) did not undergo immunoadsorption. Orthotopic lung transplants were performed through a left thoracotomy. Main pulmonary artery blood flow and pressure, left pulmonary artery blood flow, and left atrial pressure were recorded. RESULTS: At 1 hour after reperfusion, pulmonary artery graft flows and pulmonary vascular resistances (PVR) were better in animals depleted of alphaGAb than in controls (605 +/- 325.2 mL/min versus 230 +/- 21 mL/min; 27.1 +/- 41.3 mmHg/L/min versus 63 +/- 1 mmHg/L/min). But at 3 hours after reperfusion average graft flows in baboons depleted of alphaGAb had decreased to 277.6 +/- 302.2 mL/min and PVRs had increased 58.3 +/- 42.0 mmHg/L/min. On the other hand, controls maintained stable flows and PVRs (223 +/- 23 mL/min; 61 +/- 3 mmHg/L/min). Survival was ultimately better in control baboons when compared with alphaGAb depleted ones (12.2 +/- 3.3 h versus 4.4 +/- 3.2 h). CONCLUSION: Unlike heart and kidney xenograft transplants, hyperacute lung xenograft dysfunction seems to be mediated by factors other than alphaGAb.