Bacteria of the genus Shigella carry a large, low-copy virulence plasmid that encodes a type III secretion system required to cause enteroinvasive disease. Loss of the plasmid occurs readily in the laboratory and renders the bacteria avirulent. Critically, plasmid loss occurs at different rates depending upon the Shigella species, and correlates with differences in those species’ socioeconomic distribution. We have identified a novel toxin-antitoxin system that is present on the S. flexneri virulence plasmid but absent in a related species, S. sonnei. This TA system is responsible for plasmid maintenance at temperatures encountered outside of the human host, and its absence likely reflects an apparent “niche restriction” observed in S. sonnei.