In this study, the ability of synthetic fluorinated lipospermines to bind DNA and siRNA was investigated and the transfection efficiency and toxicity of the resulting lipoplexes in cell lines were evaluated. Three lipopolyamines displaying fluorous tags close to their cationic polar head ("HFP" polyamines) were synthesized. Their ability to condense pDNA and siRNA, and to form nanoparticles were characterized. Lipoplex stability was investigated in the presence of different surface active compounds and was shown to be significantly improved due to the presence of the fluorous tags. Transfection efficiencies were studied in HepG2 and 911 cell lines, and compared to that of DOGS, DOTAP, and LipofectamineÔ 2000. Also, the ability of these compounds to deliver nucleic acids into cells in the presence of high concentration of serum was quantified. By incorporating two fluorous tags in the direct vicinity of the polycationic head group of the lipospermines, we show efficient pDNA and siRNA formulation, and delivery to cultured cells. Fluorinated lipoplexes exhibit improved stability in the presence of amphiphilic compounds and retain high transfection efficiency in the presence of 50e75% serum. These results demonstrate that lipospermines displaying fluorous tags close to their cationic polar head bind to and deliver pDNA and siRNA with high cell viability in different cell lines. They are efficient non-viral vectors that exhibit remarkable serum compatibility.