Virulent Mycobacterium tuberculosis (Mtb) induces a maladaptive cytolytic death modality, necrosis, which is advantageous for the pathogen. We report that necrosis of macrophages infected with the virulent Mtb strains H37Rv and Erdmann depends on predominant LXA₄ production that is part of the antiinflammatory and inflammation-resolving action induced by Mtb. Infection of macrophages with the avirulent H37Ra triggers production of high levels of the prostanoid PGE₂, which promotes protection against mitochondrial inner membrane perturbation and necrosis. In contrast to H37Ra infection, PGE₂ production is significantly reduced in H37Rv-infected macrophages. PGE₂ acts by engaging the PGE₂ receptor EP2, which induces cyclic AMP production and protein kinase A activation. To verify a role for PGE₂ in control of bacterial growth, we show that infection of prostaglandin E synthase (PGES)^−/− macrophages in vitro with H37Rv resulted in significantly higher bacterial burden compared with wild-type macrophages. More importantly, PGES^−/− mice harbor significantly higher Mtb lung burden 5 wk after low-dose aerosol infection with virulent Mtb. These in vitro and in vivo data indicate that PGE₂ plays a critical role in inhibition of Mtb replication.