In the present study, we analyzed the role of purinergic P2X7 receptor in Mycobacterium tuberculosis infection and host interaction mechanisms in vitro and in vivo. For experimental procedures, a macrophage murine cell line RAW 264.7, and male Swiss, wild-type C57BL/6 and P2X7 receptor knockout (P2X7R −/− ) mice were used throughout this study. We have demonstrated that treatment of RAW 264.7 cells with ATP (3 and 5mM) resulted in a statistically significant reduction of M. tuberculosis-colony-forming units. The purinergic P2X7 receptor expression was found significantly augmented in the lungs of mice infected with M. tuberculosis H37Rv. Infected wild-type mice showed a marked increase in the spleen weight, in comparison to non-infected animals. Furthermore, M. tuberculosis-infected P2X7R −/− mice showed an increase of M. tuberculosis burden in lung tissue, when compared to infected wild-type mice. In P2X7R −/− spleens, we observed a significant decrease in the populations of Treg (CD4 + Foxp3 + ), T cells (CD4 + , CD8 + CD25 + and CD4 + CD25 + ), dendritic cells (CD11c + ) and B220 + cells. However, a significant increase in CD11b + cells was observed in P2X7R −/− mice, when compared to wild-type animals. In the lungs, P2X7R −/− M. tuberculosis-infected mice exhibited pulmonary infiltrates containing an increase of Treg cells (CD4 + Foxp3 + ), T cells (CD4 + and CD8 + ) and a decrease in the B220 + cells, when compared with wild-type M. tuberculosis-infected mice. The findings observed in the present study provide novel evidence on the role of P2X7 receptors in the pathogenesis of tuberculosis.