Mycobacterium tuberculosis overcomes macrophage bactericidal activities and persists intracellularly. One mechanism by which M. tuberculosis avoids macrophage killing might be through inhibition of IFN-γ-mediated signaling. In this study we provide evidence that at least two distinct components of M. tuberculosis, the 19-kDa lipoprotein and cell wall peptidoglycan (contained in the mycolylarabinogalactan peptidoglycan (mAGP) complex), inhibit macrophage responses to IFN-γ at a transcriptional level. Moreover, these components engage distinct proximal signaling pathways to inhibit responses to IFN-γ: the 19-kDa lipoprotein inhibits IFN-γ signaling in a Toll-like receptor (TLR) 2-dependent and myeloid differentiation factor 88-dependent fashion whereas mAGP inhibits independently of TLR2, TLR4, and myeloid differentiation factor 88. In addition to inhibiting the induction of specific IFN-γ responsive genes, the 19-kDa lipoprotein and mAGP inhibit the ability of IFN-γ to activate murine macrophages to kill virulent M. tuberculosis without inhibiting production of NO. These results imply that inhibition of macrophage responses to IFN-γ may contribute to the inability of an apparently effective immune response to eradicate M. tuberculosis.