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ABSTRACTIn many bacteria, the FtsH protease and its modulators, HflK and HflC, form a large protein complex that contributes to both membrane protein quality control and regulation of the cellular response to environmental stress. Both activities are crucial to the Lyme disease pathogen Borrelia burgdorferi, which depends on membrane functions, such as motility, protein transport, and cell signaling, to respond to rapid changes in its environment. Using an inducible system, we demonstrate that FtsH production is essential for both mouse and tick infectivity and for in vitrogrowth of B. burgdorferi. FtsH depletion in B. burgdorfericells resulted in membrane deformation and cell death. Overproduction of the protease did not have any detectable adverse effects on B. burgdorferigrowth in vitro, suggesting that excess FtsH does not proteolytically overwhelm its substrates. In contrast, we did not observe any phenotype for cells lacking the protease modulators HflK and HflC (ΔHflK/C), although we examined morphology, growth rate, growth under stress conditions, and the complete mouse-tick infectious cycle. Our results demonstrate that FtsH provides an essential function in the life cycle of the obligate pathogen B. burgdorferibut that HflK and HflC do not detectably affect FtsH function.IMPORTANCELyme disease is caused by Borrelia burgdorferi, which is maintained in nature in an infectious cycle alternating between small mammals and Ixodesticks. B. burgdorferiproduces specific membrane proteins to successfully infect and persist in these diverse organisms. We hypothesized that B. burgdorferihas a specific mechanism to ensure that membrane proteins are properly folded and biologically active when needed and removed if improperly folded or dysfunctional. Our experiments demonstrate that FtsH, a protease that fulfills this role in other microorganisms, is essential to B. burgdorferiviability. Cells depleted of FtsH do not survive in laboratory culture medium and cannot colonize mice or ticks, revealing an absolute requirement for this protease. However, the loss of two potential modulators of FtsH activity, HflK and HflC, does not detectably affect B. burgdorferiphysiology. Our results provide the groundwork for the identification of FtsH substrates that are critical for the bacterium’s viability.