Infection of macrophages by Mycobacterium tuberculosis drives programmed cell death and apoptosis. The cellular response to infection is phosphorylation of JAK and STAT proteins; phosphorylated STAT1 (P-STAT1) has an important pro-apoptotic activity at the onset of infection. P-STAT1 upregulates several genes that trigger apoptosis, which leads to the elimination of infected cells by the immune system. However, macrophages that were infected with Mycobacterium tuberculosis reduce levels of apoptosis and survive over time through immune evasion. Further, an increase in the levels of non-phosphorylated STAT1 is observed over long periods after infection, although its role is currently unclear. In this issue (p. 1740), Yong Zhang and colleagues show that the level of non-phosphorylated STAT1 correlates with the level of M. tuberculosis at later stages of infection. The authors also report that, when STAT1 is overexpressed, the resulting increased levels of non-phosphorylated STAT1 reduce apoptosis after infection, leading to the activation of several anti-apoptotic effectors. In particular, non-phosphorylated STAT1 interacts with STAT3 to repress the gene encoding the pro-apoptotic CD95 (FAS) and competes with IFIT1 for binding to eEF1A, which inhibits apoptosis. This work establishes an anti-apoptotic role for the non-phosphorylated form of STAT1 – in contrast to P-STAT1 – and provides an insight into the mechanisms of immune invasion of M. tuberculosis upon macrophage infection.