RNA interference (RNAi) technology provides a powerful, yet selective, molecular tool to reduce the expression of genes in eukaryotic cells. Despite the success associated with the effective use of siRNA duplexes for gene silencing, there is a need to improve their properties. These properties, related mainly to migration through the cell membranes, stability of siRNA in vivo, and specificity of their silencing activity, can be improved by chemical modifications of siRNA backbone. In this study, we examined the physicochemical and biological properties of siRNA duplexes targeted against BACE1 gene modified at various positions with a lipophilic boron cluster (C2B10H11, CB). The lipophilicity and resistance to enzymatic degradation of the modified oligomers was higher than the unmodified counterparts. As measured in a dual fluorescence assay (BACE1-GFP/RFP), the carboranyl siRNAs (CB-siRNAs) were as active as the parent nonmodified duplexes and their toxicity toward HeLa cells was also similar. The helical structure of CB-siRNAs remained unchanged upon boron cluster introduction, as determined by CD and UV melting experiments.