Pulmonary transplantation is currently limited by the number of suitable cadaver donor lungs. For this reason, pulmonary xenotransplantation is currently being investigated. Objective: Our goal was to assess the role of complement in pulmonary, xenograft dysfunction. Methods: The pulmonary function of swine expressing human decay accelerating factor and human CD59 (n = 6) was compared with that of the lungs from nontransgenic (control) swine (n = 6) during perfusion with human plasma. Results: After 2 hours of perfusion, the pulmonary vascular resistance was 1624 ± 408 dynes · sec · cm-5 in control lungs and 908 ± 68 dynes · sec · cm-5 in transgenic lungs (p < 0.05). Control lungs had a venous oxygen tension of 271 ± 23 mm Hg with a ratio of venous oxygen tension to inspired oxygen fraction of 452 ± 38 at 2 hours of perfusion; transgenic lungs had a venous oxygen tension of 398 ± 11 mm Hg and a ratio of venous oxygen tension to inspired oxygen fraction of 663 ± 18 (p < 0.05). Control lungs showed a decrease of 79.8% ± 3.7% in static pulmonary compliance by 2 hours, versus a 12.0% ± 8.1% decrease by the transgenic lungs (p < 0.05). The control lungs also developed 561.7 ± 196.2 ml of airway edema over 2 hours, in contrast to 6.5 ± 1.7 ml in transgenic lungs (p < 0.05). Conclusion: Lungs from swine expressing human decay accelerating factor and human CD59 functioned better than nontransgenic swine lungs when perfused with human plasma. These results suggest that complement activation is involved in producing acute pulmonary xenograft dysfunction and demonstrate that lungs from swine expressing human decay accelerating factor and human CD59 are protected against pulmonary injury when perfused with human plasma.