<jats:title>SUMMARY</jats:title><jats:p>Mucosal-associated invariant T (MAIT) cells are a subset of innate T lymphocytes activated by bacteria that produce vitamin B2 metabolites. Mouse models of infection have demonstrated a role for MAIT cells in antimicrobial defence. However, proposed protective roles of MAIT cells in human infections remain unproven and clinical conditions associated with a selective absence of MAIT cells have not been identified. We report that typhoidal and non-typhoidal <jats:italic>S. enterica</jats:italic> strains generally activate MAIT cells. However, African invasive disease-associated multidrug-resistant <jats:italic>S.</jats:italic> Typhimurium sequence type 313 lineage 2 strains escape MAIT cell recognition through overexpression of <jats:italic>ribB</jats:italic>, a bacterial gene that encodes the 4-dihydroxy-2-butanone 4-phosphate synthase enzyme of the riboflavin biosynthetic pathway. This MAIT cell-specific phenotype did not extend to other innate lymphocytes. We propose that <jats:italic>ribB</jats:italic> overexpression is an evolved trait that facilitates evasion from immune recognition by MAIT cells and contributes to the invasive pathogenesis of <jats:italic>S.</jats:italic> Typhimurium sequence type 313 lineage 2 <jats:italic>in vivo</jats:italic>.</jats:p>