Infection with the human pathogen Salmonella Typhi has been modelled in mice—normally resistant to S. Typhi infection. Toll-like receptor 11 (TLR11), expressed in mice but not humans, recognizes bacterial flagellin and triggers a protective immune response. In this study, tlr11−/− mice were found to be susceptible to infection following oral delivery of S. Typhi; these mice could also be successfully immunized. The tlr11−/− model might provide new insights into the immune response to S. Typhi and promote vaccine development.