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New control measures are urgently required to control tuberculosis (TB), as the current vaccine, Bacille Calmette–Guérin (BCG), has had a limited impact on disease spread. The identification of virulence mechanisms of <i>Mycobacterium tuberculosis</i> is an important strategy in vaccine design, as it permits the development of strains attenuated for growth that may have vaccine potential. In this report, we determined the role of the PdtaS response regulator in <i>M. tuberculosis</i> virulence and defined the vaccine potential of a <i>pdtaS</i>-deficient strain. Deletion of <i>pdtaS</i> (<i>Mtb</i>^ΔpdtaS) resulted in reduced persistence of <i>M. tuberculosis</i> within mouse organs, which was equivalent to the persistence of the BCG vaccine in the lung and liver of infected mice. However, the generation of effector CD4⁺ and CD8⁺ T cells (CD44⁺CD62L^loKLRG1⁺) was similar between wild-type <i>M. tuberculosis</i> and <i>Mtb</i>^ΔpdtaS and greater than that elicited by BCG. Heightened immunity induced by <i>Mtb</i>^ΔpdtaS compared to BCG was also observed by analysis of antigen-specific IFN-γ-secreting T cell responses induced by vaccination. <i>Mtb</i>^ΔpdtaS displayed improved protection against aerosol <i>M. tuberculosis</i> compared to BCG, which was most apparent in the lung at 20 weeks post-infection. These results suggest that the deletion of the PdtaS response regulator warrants further appraisal as a tool to combat TB in humans.