<jats:title>ABSTRACT</jats:title> <jats:p> <jats:named-content content-type="genus-species">Francisella tularensis</jats:named-content> is a facultative intracellular, Gram-negative pathogen and the causative agent of tularemia. We previously identified TolC as a virulence factor of the <jats:named-content content-type="genus-species">F. tularensis</jats:named-content> live vaccine strain (LVS) and demonstrated that a Δ <jats:italic>tolC</jats:italic> mutant exhibits increased cytotoxicity toward host cells and elicits increased proinflammatory responses compared to those of the wild-type (WT) strain. TolC is the outer membrane channel component used by the type I secretion pathway to export toxins and other bacterial virulence factors. Here, we show that the LVS delays activation of the intrinsic apoptotic pathway in a TolC-dependent manner, both during infection of primary macrophages and during organ colonization in mice. The TolC-dependent delay in host cell death is required for <jats:named-content content-type="genus-species">F. tularensis</jats:named-content> to preserve its intracellular replicative niche. We demonstrate that TolC-mediated inhibition of apoptosis is an active process and not due to defects in the structural integrity of the Δ <jats:italic>tolC</jats:italic> mutant. These findings support a model wherein the immunomodulatory capacity of <jats:named-content content-type="genus-species">F. tularensis</jats:named-content> relies, at least in part, on TolC-secreted effectors. Finally, mice vaccinated with the Δ <jats:italic>tolC</jats:italic> LVS are protected from lethal challenge and clear challenge doses faster than WT-vaccinated mice, demonstrating that the altered host responses to primary infection with the Δ <jats:italic>tolC</jats:italic> mutant led to altered adaptive immune responses. Taken together, our data demonstrate that TolC is required for temporal modulation of host cell death during infection by <jats:named-content content-type="genus-species">F. tularensis</jats:named-content> and highlight how shifts in the magnitude and timing of host innate immune responses may lead to dramatic changes in the outcome of infection. </jats:p>