Acute rejection and graft arteriopathy in cardiac transplantation limit the long-term survival of recipients; these processes are enhanced by several cytokines and adhesion molecules. Nuclear factor-kappa B (NFκB) is critical in the transcription of multiple genes involved in inflammation and cell proliferation. To test the hypothesis that NFκB decoy can attenuate acute rejection and arteriopathy, we performed single intraluminal delivery of NFκB decoy into murine cardiac allografts using a hemagglutinating virus of Japan (HVJ)-artificial viral envelope (AVE)-liposome method. No decoy or scrambled decoy transfer was performed for control. Hearts were heterotopically transplanted from BALB/c to C3H/He mice (major mismatch group) and from DBA/2 to B10. D2 mice (minor mismatch group). Nontreated or scrambled decoy transfected allografts of the major mismatch group were acutely rejected, while NFκB decoy prolonged their survival. While severe cell infiltration and intimal thickening with enhancement of inflammatory factors were observed in untreated or scrambled decoy-treated allografts of minor mismatch group at day 28, NFκB decoy attenuated these changes. We conclude that NFκB is critically involved in the development of acute as well as chronic rejection of the transplanted hearts. NFκB decoy attenuates both acute rejection and graft arteriopathy by blocking the activation of several genes.