Mycobacterium tuberculosis-induced macrophage apoptosis can be inhibited by mannosylated lipoarabinomannan (ManLAM), although it induces tumor necrosis factor (TNF)-α and NO production, which participate in apoptosis induction. ManLAM also modulates Ca+2-dependent intracellular events, and Ca+2 participates in apoptosis in different systems. Ca+2 was assessed for involvement in M. tuberculosis-induced macrophage apoptosis and for modulation by ManLAM. The role of Ca+2 was supported by the blockade of apoptosis by cAMP inhibitors and the Ca+2 chelator, BAPTA/AM. These agents also inhibited caspase-1 activation and cAMP-responsive element-binding protein translocation without affecting TNF-α production. Infection of macrophages with M. tuberculosis induced an influx of Ca+2 that was prevented by ManLAM. Similarly, M. tuberculosis infection-altered mitochondrial permeability transition was prevented by ManLAM and BAPTA/AM. Finally, ManLAM and BAPTA/AM reversed the effects of M. tuberculosis on p53 and Bcl-2 expression. ManLAM counteracts the alterations of calcium-dependent intracellular events that occur during M. tuberculosis-induced macrophage apoptosis.