The rpoS (katF) gene, which encodes a RNA polymerase sigma factor (sigma s), regulates the virulence of Salmonella typhimurium in mice. In the present study, we show that rpoS mutants can be frequently found among laboratory strains of Salmonella. In addition, a rpoS mutation was identified in the S. typhi live oral vaccine Ty21a. Introduction of a wild-type rpoS gene in Ty21a allowed the bacteria to survive better under starvation conditions and increased their resistance to other stresses. These results contribute to a better understanding of the genetic background of the live typhoid oral vaccine Ty21a and suggest that the rpoS mutation may contribute to the safety of this strain in humans.