Shigella flexneri is an enteroinvasive bacterium responsible for bacillary dysentery in humans. Bacterial entry into epithelial cells is a crucial step for the establishment of the infection. It is characterized by a transient reorganization of the host cell cytoskeleton at the site of bacterial interaction with the cell membrane, which leads to bacterial engulfment by a macropinocytic process. We show in this study that the membrane-cytoskeleton linker, ezrin, a member of the ERM (ezrin, radixin, moesin) family, plays an active role in the process of Shigella uptake. Ezrin is highly enriched in cellular protrusions induced by the bacterium and is found in close association with the plasma membrane. In addition, Shigella entry is significantly reduced in cells transfected with a dominant negative allele of ezrin with entry foci showing much shorter cellular protrusions. These results indicate that ezrin not only acts as a membrane-cytoskeleton linker, but may also mediate extension of cellular projections in the presence of signals such as those elicited by invading microorganisms.