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Allograft injury is a major risk factor for death in lung transplant recipients. Complement protein C3 is primarily synthesized in the liver. However, a recent study by our group has demonstrated that C3 present in pulmonary epithelial cells can be augmented to facilitate their own ability to withstand acute environmental stress. Here, we hypothesized that pulmonary C3 expression reduces the severity of allograft rejection. To address this question, C3−/−left lungs [on a C57BL/6 (B6) background] were orthotopically transplanted into wildtype (WT) fully MHC mismatched (CBA/J) recipients. The right lung, native to the recipient, served as an internal control. CBA/J lungs transplanted into C3−/− recipients, C3−/− lungs transplanted into C3−/− recipients and CBA/J lungs transplanted into WT B6 recipients were also employed as controls. One week after transplantation, recipients were euthanized and evaluated for C3 levels and graft injury. C3 protein in C3−/− recipients of WT B6 and CBA/J lungs was not detected in the peripheral circulation but was expressed within graft tissues suggesting locally expressed C3 is sequestered within the lung. Signs of graft tissue injury were only observed in allogeneic recipients. However, acute rejection severity was significantly higher in C3−/− allografts when compared to WT allografts. Additionally, C3−/− allografts had a distinct pattern of acute alveolar damage and increased cellularity not evident in WT allografts. Taken collectively, our data indicate that expression of C3 by lung allografts attenuates alloimmunedependent responses that are associated with reduced survival in humans.