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The cell wall of <i>Mycobacterium tuberculosis</i> is composed of unique lipids that are important for pathogenesis. Indeed, the first-ever genetic screen in <i>M. tuberculosis</i> identified genes involved in the biosynthesis and transport of the cell wall lipid PDIM (<i>p</i>hthiocerol <i>dim</i>ycocerosates) as crucial for the survival of <i>M. tuberculosis</i> in mice. Here we show evidence for a novel molecular mechanism of the PDIM-mediated virulence in <i>M. tuberculosis</i> We characterized the DNA interaction and the regulon of Rv3167c, a transcriptional repressor that is involved in virulence regulation of <i>M. tuberculosis</i>, and discovered that it controls the PDIM operon. A loss-of-function genetic approach showed that PDIM levels directly correlate with the capacity of <i>M. tuberculosis</i> to escape the phagosome and induce host cell necrosis and macroautophagy. In conclusion, our study attributes a novel role of the cell wall lipid PDIM in intracellular host cell modulation, which is important for host cell exit and dissemination of <i>M. tuberculosis</i><b>IMPORTANCE</b><i>Mycobacterium tuberculosis</i> is a major human pathogen that has coevolved with its host for thousands of years. The complex and unique cell wall of <i>M. tuberculosis</i> contains the lipid PDIM (<i>p</i>hthiocerol <i>dim</i>ycocerosates), which is crucial for virulence of the bacterium, but its function is not well understood. Here we show that PDIM expression by <i>M. tuberculosis</i> is negatively regulated by a novel transcriptional repressor, Rv3167c. In addition, we discovered that the escape of <i>M. tuberculosis</i> from its intracellular vacuole was greatly augmented by the presence of PDIM. The increased release of <i>M. tuberculosis</i> into the cytosol led to increased host cell necrosis. The discovery of a link between the cell wall lipid PDIM and a major pathogenesis pathway of <i>M. tuberculosis</i> provides important insights into the molecular mechanisms of host cell manipulation by <i>M. tuberculosis</i>.