Introduction NSAIDs have been shown to have anti-tumor effects in animal and clinical studies. Recent evidences suggest that anti-proliferative effects can be exerted through COX-independent pathway. Previous studies have demonstrated that celecoxib induces apoptosis by inhibiting Akt activation. We examined the effects of celecoxib on neointimal formation after balloon injury and its action mechanism. Methods In-vitro, we evaluated the effects of celecoxib on Akt/GSK axis and viability of rat vascular smooth muscle cell(VSMC). Then in-vivo, we compared the effect of celecoxib(50mg/kg), aspirin(50mg/kg), and vehicle in three groups (n=15/group) of male rats (13wks) that underwent denudation injury of carotid artery with 2F Fogarty catheter. Treatment was started 3 days before injury and continued for 2weeks after injury. The effect of drugs was evaluated at 3d and 2wk. Results In-vitro, celecoxib significantly suppressed the level of phospho-Akt and phospho-GSK in immunoblot analysis of rat VSMC, which led to the decreased number of viable cells. In in-vivo experiment, at 3d after balloon injury, celecoxib significantly decreased the injury-induced phosphorylation of Akt and GSK in Western blot analysis, which led to the decreased proliferation of VSMC in immunohistochemistry(IHC) for PCNA and the increased apoptosis of VSMC in TUNEL assay, whereas aspirin showed no effect. In morphometry at 2wk, celecoxib significantly decreased the ratio of Intima to Media (I/M) (vehicle vs celecoxib 0.98짹0.15 vs 0.47짹0.18 p<0.05), whereas aspirin didn't show any effect. To corroborate that the inhibition of Akt by celecoxib is the key mechanism for suppression of neointimal formation, we delivered adenoviral vector expressing dominant-negative(DN) Akt gene to rat carotid artery after balloon injury. Gene transfer of DN-Akt significantly inhibited neointimal formation (I/M ratio: Control vs DN-Akt, 0.81짹0.19 vs 0.39짹0.22, p<0.05). Conclusions Celecoxib is a potential inhibitor of neointimal formation, whereas aspirin is not, through blocking of the injury-induced activation of Akt. Our findings suggest the novel clinical usage of celecoxib, such as prevention of restenosis after angioplasty.