SID-1 is a transmembrane protein that mediates systemic RNA interference in Caenorhabditis elegans. Here we show that the mammalian SID-1 homologue FLJ20174 localizes to the cell membrane of human cells and enhances their uptake of small interfering RNA (siRNA), resulting in increased siRNA-mediated gene silencing efficacy. This is the first demonstration to show that overexpression of a membrane protein enhances siRNA internalization in mammalian cells. This observation raises the possibility of enhancing the efficacy of RNA interference. © 2005 Elsevier Inc. All rights reserved.