The Vi capsular polysaccharide is a virulence-associated factor expressed by Salmonella enterica serotype Typhi but absent from virtually all other Salmonella serotypes. In order to study this determinant in vivo, we characterised a Vi-positive S. Typhimurium (C5.507 Vi +), harbouring the Salmonella pathogenicity island (SPI)-7, which encodes the Vi locus. S. Typhimurium C5.507 Vi + colonised and persisted in mice at similar levels compared to the parent strain, S. Typhimurium C5. However, the innate immune response to infection with C5.507 Vi + and SGB1, an isogenic derivative not expressing Vi, differed markedly. Infection with C5.507 Vi + resulted in a significant reduction in cellular trafficking of innate immune cells, including PMN and NK cells, compared to SGB1 Vi - infected animals. C5.507 Vi + infection stimulated reduced numbers of TNF-α, MIP-2 and perforin producing cells compared to SGB1 Vi -. The modulating effect associated with Vi was not observed in MyD88 -/- and was reduced in TLR4 -/- mice. The presence of the Vi capsule also correlated with induction of the anti-inflammatory cytokine IL-10 in vivo, a factor that impacted on chemotaxis and the activation of immune cells in vitro.