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We chemically synthesized two different cationic lipids consisting of a core of lysine, two C-14 hydrocarbon chains, and either aspartatic acid or glutamic acid. The lipids were assigned the acronyms, DMKD and DMKE. Cationic liposomes prepared with the two different lipids were tested for their gene-transferring capabilities in various cell lines compared with that of control DOTAP liposomes. Under the same experimental conditions, the order of in vitro gene transfection efficiency was DMKE≥DMKD>DOTAP. To identify the parameters influencing transfection efficiency, the DNA-binding affinities of the liposomes were compared and changes in particle size and surface charge were examined after complex formation. Both the DNA-binding affinity of the liposomes and the cell surface-binding affinity of the liposome-pDNA complexes were crucial for gene transfection. In addition, intravenously administered DMKE and DMKD liposomes exhibited different biodistribution characteristics and intensity of in vivo organ transfection from the DOTAP liposomes. Compared to the DOTAP liposomes, they were more readily transferred to the liver. Interestingly, when they were directly injected into tumor tissues, the DMKE lipoplexes were able to induce more efficient transgene expression in these tissues than the DOTAP and DMKD lipoplexes. This study suggests that a small difference in the cationic lipid backbone structure significantly affects gene-transferring capabilities. DMKE and DMKD liposomes can be utilized as efficient gene-transferring vehicles for hepatic or intra-tumoral gene transfection.