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Skeletal muscle is an interesting target for gene therapy. To achieve effective gene introduction in skeletal muscle, a hydrodynamic approach by intravenous injection of plasmid DNA (pDNA) with transient isolation of the limb has attracted attention. In this study, we demonstrated that polyplex nanomicelle, composed of poly(ethyleneglycol) (PEG)-block-polycation and pDNA, showed excellent capacity of gene introduction to skeletal muscle. The evaluation of luciferase expression in the muscle revealed that the nanomicelle provided higher and sustained profiles of transgene expression compared with naked pDNA. Real-time in vivo imaging using a video-rate confocal imaging system suggested that the nanomicelle showed tolerability in the intracellular environment, resulting in the slow but sustained transgene expression. The nanomicelle induced less TNFα induction in the muscle than naked pDNA, indicating the safety of nanomicelle-based gene delivery into the skeletal muscle. Moreover, the nanomicelle showed significant tumor growth suppression for almost a month by introducing a pDNA expressing a soluble form of vascular endothelial growth factor (VEGF) receptor-1 (sFlt-1) to skeletal muscle to obtain anti-angiogenic effect on tumor growth. This feature of sustained effect gives an important advantage of gene therapy, especially on the points of cost effectiveness and high compliance. These results suggest that the hydrodynamic gene introduction to skeletal muscle using polyplex nanomicelle system possesses the potential for effective gene therapy.