Mycobacterium tuberculosis (MTB) is a monocyte/macrophage (M/M) parasite, which has developed several mechanisms to survive and multiply intracellularly. On the other hand, infected cells are engaged in the effort to reduce mycobacterial viability. On this ground, we report that MTB infection predisposes M/M to a pro-apoptotic ATP-based signalling, which is aimed at decreasing MTB replication. In fact, we show that mycobacterial infection leads to an increased expression of P2X(7) purinergic receptors, which is paralleled by intracellular accumulation and subsequent extracellular release of ATP by infected macrophages. Activation of this signal is conceived to induce apoptosis in MTB-infected cells, since blocking P2X(7) receptor by means of oxidized ATP (oATP) prevents MTB induced cell death. Finally, we show that an ATP stimulation of MTB-infected M/M, besides increasing cellular apoptosis, strongly enhances intracellular MTB killing, as evaluated through Colony Forming Unit assay, and such effect is subverted through oATP pulsing of infected cells. Taken together, our data indicate a role of P2X(7) purinergic receptors in MTB-induced M/M apoptosis, suggesting the existence of an autocrine/paracrine loop leading to apoptosis of infected M/M and the feasible protective role of ATP-triggered cell death in tuberculosis.