Aim To investigate the effects of siRNA recombinant lentivirus targeting CREB binding protein （CBP） gene on neointimal hyperplasia in rat carotid arteries after balloon injury and its possible mechanism. Methods Forty-eight male SD rats were randomly divided into four groups: Sham group, PBS group, CBP-siRNA-Lentivirus group and NC-siRNA-Lentivirus group to establish the model of balloon-injury in left common carotid artery, and the rats were sacrificed 28 days after injury and in vivo gene transfer. The expression of CBP and acetylated nuclear factor kappaB p65 （NF-κB p65） were determined by real-time PCR and Western Blot. Proliferating cell nuclear antigen （PCNA） protein expression was detected by immunohistochemistry. Meanwhile, morphometric analysis was used to measure neointimal hyperplasia. Results 28 days after operations, lentivirus siRNA targeting CBP markedly decreased CBP mRNA and protein expression compared with PBS and NC-siRNA-Lentivirus groups（P<0.05）. CBP gene silencing significantly reduced the neointimal area （0.108±0.008 mm² vs 0.238±0.022 mm² and 0.252±0.016 mm², P<0.05） and intima / media ratio （0.706±0.062 vs 1.483±0.136 and 1.497±0.137, P<0.05）. Furthermore, compared with PBS and NC-siRNA-Lentivirus groups, PCNA and acetylation of NF-κB p65 expression were both obviously downregulated in CBP-siRNA-Lentivirus group （P<0.05）. Conclusions Lentivirus-mediated CBP gene silencing could efficiently suppress neointimal formation in balloon injured rat carotid artery, and the mechanism was involved with downregulation of NF-kB p65 acetylation.