Resistance and susceptibility of macrophages to mycobacteria are under the control of the Bcg/Nramp1 gene, which also controls the NO- production in response to macrophage activators. There is recent evidence indicating that mycobacteria induces apoptosis in infected macrophages. Using murine macrophage lines, congenic at the Bcg/Nramp1 gene, this report shows that B10R are more prone than B10S macrophages to undergo apoptosis after exposure to live virulent Mycobacterium tuberculosis H37Rv (Mtb) or PPD, as determined by cell viability, DNA fragmentation, hypoploidy, and the terminal deoxynucleotide transferase dUTP-biotin nick-end labeling assay. Induction of apoptosis correlated with NO- production. Aminoguanidine and anti-TNF-alpha inhibited NO- production and apoptosis. B10R and B10S macrophages were equally affected by sodium nitroprusside, a donor of NO-, but its effect, mainly in B10R cells, was enhanced by the presence of Mtb. Nonvirulent mycobacteria induced lower levels of NO- and did not cause cell death. Killed Mtb, mannose-capped lipoarabinomannan (ManLAM), and LPS rescued macrophages from apoptosis albeit induce NO-. These findings suggest the existence of opposite pathways: metabolically active mycobacteria promotes apoptosis whereas their structural components inhibit it. Apoptosis may be a critical mechanism by which Nramp1 gene controls the macrophage infection with virulent mycobacteria.