Animal models of tuberculosis point to a protective role for MHC class I-restricted CD8(+) T cells, yet it is unclear how these cells protect or whether such findings extend to humans. Here we report that macrophages infected with Mycobacterium tuberculosis, rapidly process and present an early secreted antigenic target (ESAT-6)-specific HLA class I-restricted CD8(+) T cell epitope. When cocultured with CD8(+) T cells restricted through classical HLA class I molecules the growth of bacilli within macrophages is significantly impaired after 7 days. This slow antimycobacterial activity did not correlate with macrophage lysis but required cell contact. We also found that inhibitors of apoptosis either had no effect or augmented the CD8-mediated suppressive activity, suggesting that an activation signal might be involved. Indeed we show that CD8(+) T cells were able to activate macrophages through receptors that include CD95 (Fas). Consistent with these findings the CD8-mediated suppression of mycobacterial growth was partially reversed by Fas blockade. These data identify a previously unrecognized CD8(+) T cell-mediated mechanism used to control an intracellular infection of macrophages.