Novel lipid derivatives carrying amino and triazolyl groups were efficiently synthesized and covalently anchored at the 3'-termini of oligonucleotides. The desired amino-lipid conjugates were fully characterized by reversed-phase HPLC and MALDI-TOF mass spectrometry. The methodology was applied to the synthesis of lipid-siRNA designed to inhibit tumor necrosis factor (TNF-α) in order to obtain siRNAs with anti-inflammatory properties. The siRNA duplex carrying amino-lipids at the 3'-end of the passenger strand has inhibitory properties similar to those of unmodified RNA duplexes in HeLa cells, indicating that the new lipid derivatives are compatible with the RNA interference machinery.