Structural bone allografts are used to reconstruct large skeletal defects after tumor surgery. Although allograft-related complications are declining, the use of perioperative radiation therapy is associated with a poorer outcome. Recently, BMP-2 levels in the host bed were reportedly diminished after exposure to radiation doses consistent with those used perioperatively to treat musculoskeletal sarcoma. Reintroduction of this osteogenic protein may circumvent the deleterious effects of preoperative radiation on allograft incorporation. We introduced a novel polymeric BMP-2 gene delivery system into the host-allograft junctions at the time of transplantation in an ovine tibial defect model with or without preoperative exposure to 50 Gy radiation. After 4 months, we noted no radiographic or histologic improvements in allograft incorporation after preoperative radiation and BMP-2 reintroduction; however, 50 Gy radiation was associated with increased porosity in the interface regions and poorer radiographic healing. We identified no BMP2-expressing cells or protein in the interface at the study end point, suggesting the polymeric gene delivery system was unable to promote extended expression of the protein or induce a healing response. Although gene therapy may hold promise as a novel technique to improve allograft incorporation, our data do not support that contention with the current approach.