Small interfering RNAs (siRNAs) have been developed to intentionally repress a specific gene expression by directing RNA-induced silencing complex (RISC), mimicking the endogenous gene silencer, microRNAs (miRNAs). Although siRNA is designed to be perfectly complementary to an intended target mRNA, it also suppresses hundreds of off-targets by the way that miRNAs recognize targets. Until now, there is no efficient way to avoid such off-target repression, although the mode of miRNA-like interaction has been proposed. Rationally based on the model called "transitional nucleation" which pre-requires base-pairs from position 2 to the pivot (position 6) with targets, we developed a simple chemical modification which completely eliminates miRNA-like off-target repression (0%), achieved by substituting a nucleotide in pivot with abasic spacers (dSpacer or C3 spacer), which potentially destabilize the transitional nucleation. Furthermore, by alleviating steric hindrance in the complex with Argonaute (Ago), abasic pivot substitution also preserves near-perfect on-target activity (~80-100%). Abasic pivot substitution offers a general means of harnessing target specificity of siRNAs to experimental and clinical applications where misleading and deleterious phenotypes from off-target repression must be considered. [BMB Reports 2016; 49(3): 135-136].