Background: In terms of neointimal hyperplasia after vascular injury such as angioplasty, it is well known that the phenotypic change of vascular smooth muscle cells (VSMC) is one of the main mechanisms. Moreover, Protein kinase G (PKG) is known to play an important role in the process of phenotypic change of VSMCs. Rosiglitazone (RSG) is known to have pleiotrophic effect on vascular cells. Here, we examined the effects of rosiglitazone on the modulation of VSMC phenotype through PKG pathway. In addition, we tested whether RSG could reduce neointimal hyperplasia after angioplasty through PKG activation. Methods & Results: In vitro studies showed that RSG dramatically inhibited the phenotype change of VSMCs from contractile form to synthetic form. This was confirmed by IF staining for SMA, calponin, and thrombospondin as well as morphologic change. Next, Western blot showed that the reduced level of PKG by PDGF was reversed by rosiglitazone, resulting in the increase of PKG activity. The increased activity of PKG by RSG inhibited the proliferation of VSMC, which was confirmed by BrdU incorporation assay. The assay for NO activity and cGMP level demonstrated no change of the level of NO or cGMP by RSG. ChIP assay for PKG promoter showed that the activation of PKG was induced by the increase of binding of Sp1 on the promoter region of PKG. In vivo experiments with rat carotid artery injury model showed that RSG significantly inhibited the neointimal formation after balloon injury. We could confirm that this effect was driven by the inhibitory effect of RSG through the phenotypic modulation of VSMC. Conclusions: Our study demonstrated that RSG is a potent modulator of VSMC phenotype which is regulated by PKG. This activation of PKG by RSG result in reducing neointimal hyperplasia after angioplasty. These results suggest that RSG can be a potent candidate drug for drug-eluting stents.