Small interfering RNA (siRNA), an important mediator of RNA interference, has recently been recognized as a promising nucleic acid medicine for the treatment of incurable genetic disorders, cancers, and viral infections because of highly efficient sequence-specific gene silencing activity. However, clinical applications of RNA interference-based therapeutics have been limited mainly due to low intracellular delivery efficiency in vitro and in vivo. In general, naked siRNA does not freely cross the cell membrane due to its large molecular weight and polyanionic nature. Thus, the positively charged gene carriers are required to facilitate endocytosis into cytoplasm. Such cationic nanocomplexes can effectively deliver transgenes to myoblasts in culture and many different types of cells in vivo, including epithelial cells and hepatocytes. However, the effectiveness of cationic reagents on gene transfer in skeletal and cardiac muscles in vivo has been disappointing. Highly cationic nanocomplexes were even less efficient for transduction of muscle than the naked genes. The reasons for this ineffectiveness in muscles may be the interaction between the positively charged complexes and negatively charged extracellular matrix (ECM), a basement membrane rich in glycosaminoglycans, components surrounding muscle fibers within cardiac and skeletal muscles. Therefore, for successful application of siRNA therapeutics in clinical settings especially for cardiac applications, delivery systems should be more carefully designed after considering the unique properties of siRNA and muscular structure of the heart. In this study, facially amphipathic deoxycholic acid (DA)-modified low molecular weight polyethyleneimine (PEI) (DA-PEI) was synthesized and used as a potent carrier system for siRNA targeted against SH2 domain-containing phosphatases-1(SHP-1), a cytoplasmic protein tyrosine phosphatase inducing apoptotic loss of cardiomyocytes after myocardial infarction. The DA-PEI/SHP-1 siRNA complexes achieved effective target gene (SHP-1) silencing in rat cardiomyocytes (H9C2) under in vitro hypoxia conditions. Interestingly, the DA-PEI/siRNA complexes exhibited relatively high siRNA retention in myocardium after direct myocardial injection. In addition, the DA-PEI/SHP-1 siRNA polyplex formulation led to a significant decrease in SHP-1 expression in rat ischemic myocardium, resulting in the efficient suppression of cardiomyocyte apoptosis and subsequent reduction of myocardial infarction. These results suggest that the DA-PEI gene delivery system may potentially be used as an effective vector for siRNA therapeutics for various cardiac diseases.