Double-stranded short interfering RNAs (siRNAs) mediate post-transcriptional inhibition of gene expression in a variety of biological systems. However, human liver cells show poor uptake of these nucleic acids. In order to improve the delivery of siRNA into these cells without transfection agents, we have synthesized two series of lipophilic siRNAs conjugated with derivatives of cholesterol, lithocholic acid or lauric acid. The lipid moieties were covalently linked to the 5'-ends of the RNAs using phosphoramidite chemistry. The potency of these chemically modified siRNAs to inhibit reporter gene expression was further investigated in vitro with beta-galactosidase expressing liver cells.