We describe the association of caspase-dependent and caspase-independent mechanisms in macrophage apoptosis induced by LpqH, a 19 kDa Mycobacterium tuberculosis lipoprotein. LpqH triggered TLR2 activation, with upregulation of death receptors and ligands, which was followed by a death receptor signaling cascade with activation of initiator caspase 8 and executioner caspase 3. In this caspase-mediated phase, mitochondrial factors were involved in loss of mitochondrial transmembrane potential (ΔΨm), release of cytochrome c, and caspase 9 activation. Interestingly, a caspase-independent pathway was also identified; by immunoblot, the mitochondrial apoptosis inducing factor (AIF) was demonstrated in nuclei and cytosol of LpqH-treated macrophages. Confocal microscopy revealed translocation of AIF to the nuclei of the majority of apoptotic cells. These findings emphasize the complex and redundant nature of the macrophage death response to mycobacteria.