<jats:title>Abstract</jats:title><jats:p>CD8<jats:sup>+</jats:sup> T cells play a central role in immune protection against infection with <jats:italic>Mycobacterium tuberculosis</jats:italic>. One of the target epitopes for anti‐<jats:italic>M. tuberculosis</jats:italic> directedCD8<jats:sup>+</jats:sup> T cells is the HLA‐A2‐restricted 19‐kDa lipoprotein peptide VLTDGNPPEV. T cell clones directed against this epitope recognized not only the nominal peptide ligand, but also a closely related peptide (VPTDPNPPEV) from the HIV envelope gp120 (HIV<jats:sub>env</jats:sub> gp120) protein characterized by IFN‐γ release. This cross‐reactivity was confirmed in <jats:italic>ex vivo</jats:italic> in <jats:italic>M. tuberculosis</jats:italic> 19‐kDa tetramer‐sorted T cells from patients with tuberculosis and in HIVgp120 tetramer‐reactive T cells sorted from HIV<jats:sup>+</jats:sup> patients. <jats:italic>M. tuberculosis</jats:italic> 19‐kDa antigen‐reactive T cells were present in HLA‐A2<jats:sup>+</jats:sup> patients (10/10) with HIV infection with no evidence of <jats:italic>M. tuberculosis</jats:italic> infection, but they are absent in peripheral blood lymphocytes from healthy HLA‐A2<jats:sup>+</jats:sup> individuals (10/10). <jats:italic>M. tuberculosis</jats:italic> 19‐kDa antigen‐reactive T cells were elevated in acute pulmonary tuberculosis, declined with response to therapy (7/10 patients) and resided in the terminally differentiated CD8<jats:sup>+</jats:sup> T cell subset. CD8<jats:sup>+</jats:sup> cross‐reactive T cells recognizing HIV<jats:sub>env</jats:sub> or <jats:italic>M. tuberculosis</jats:italic> 19‐kDa antigens may contribute to pathogenesis in individuals co‐infected with both pathogens and may also present a marker for active tuberculosis.</jats:p>