Inflammatory response followed by vascular injury plays an important role in the development of neointima formation and atherosclerotic lesions, which is in part mediated by proinflammatory cytokines. Using a cuff injury model, we examined the effects of adenovirus-mediated overexpression of PTEN (phosphatase and tensin homology deleted on chromosome 10) on neointima formation and proinflammatory response. A cuff was placed around the femoral artery and then adenovirus expressing hPTEN1 (AdPTEN) or Escherichia coli -galactosidase (AdLacZ) was injected between the cuff and adventitia. Fourteen days later, the arteries were examined histopathologically and by Western blotting. As a result, AdPTEN significantly reduced neointima formation compared with AdLacZ, accompanied by reduced cell proliferation and increased adventitial cell apoptosis. AdPTEN also reduced the expression level of phospho-IB- but not IB- . Western blotting revealed that AdPTEN reduced the cuff injury-induced expression levels of monocyte chemoattractant protein-1 (MCP-1), TNF- and IL-1, and their expression in all layers of the arterial wall. In contrast, cuff-induced macrophage invasion, which was also inhibited by AdPTEN, was detected only in the intimal surface and adventitia. In cultured vascular smooth muscle cells (VSMCs), PTEN directly inhibited ANG II-induced MCP-1 expression quantified by real-time PCR and Western blotting. Our results suggest that overexpression of PTEN reduces neointima formation, possibly in part through inhibition of inflammatory response involving macrophage invasion and proinflammatory cytokine expression.