Differential induction of cell death in mycobacteria-infected monocytes and macrophages has been invoked as one possible mechanism by which some tumor necrosis factor (TNF)-targeted biologicals reactivate tuberculosis more frequently than others. We infected primary human monocytes and monocyte-derived macrophages with the virulent Mycobacterium tuberculosis strain H37Rv and followed the rate of cell death in the absence or presence of a wide concentration range of four different TNF-targeted biologicals: infliximab and adalimumab (both monoclonal antibodies to human TNF) and etanercept and polyethylene-glycols TNFR1 (fusion constructs of human TNFR2 and TNFR1, respectively). None of the TNF-targeted biologicals used modulated the death rate of monocytes/macrophages induced by infection with M. tuberculosis alone. Our data support the view that mycobacteria-induced cell death is largely independent of TNF and that the primary target for differential modulation by TNF-targeted biologicals during tuberculosis is not a recently recruited monocyte or freshly differentiated macrophage.