Salmonella Typhi is a human-host restricted pathogen, responsible for typhoid fever in approximately 10.9 million people annually1. The typhoid-toxin is postulated to have a central role in disease pathogenesis, establishment of chronic infection and human-host restriction2–6. However, its precise typhoid-toxin in acute infection using a randomised, double-blinded Salmonella Typhi human-challenge model7. Forty healthy volunteers were randomised (1:1) to oral challenge with 104 colony forming units (CFU) of wild-type (WT) or an isogenic typhoid-toxin deletion mutant (TN) of Salmonella Typhi. We observed no significant difference in the rate of typhoid infection (fever ≥38oC for ≥12 hours and/or S. Typhi bacteremia) between participants challenged with WT or TN S. Typhi (15/21 [71%] vs. 15/19 [79%]; p = 0.58). Theduration of bacteremia was significantly longer in participants challenged with the TN strain compared with WT. The clinical syndrome was otherwise indistinguishable between WT and TN groups. These data suggest that the typhoid-toxin is not required for infection and the development of early typhoid fever symptoms within the context of a human-challenge model. Further clinical data are required toassess the role of typhoid-toxin in severe disease or establishment of bacterial carriage.