Updated project metadata. Extracellular Mycobacterium tuberculosis (Mtb) aggregates can evade phagocytosis and intracellular host-cell defenses by inducing macrophage killing. We showed that Mtb aggregates require a functional ESX-1 type VII secretion system and production of the surface-exposed lipid phthiocerol dimycocerosate (PDIM) to induce cell death upon contact with macrophages. We used quantitative proteomics to compare the secretome of a panel of Mtb mutant strains that induce or do not induce macrophage death and identified secreted bacteria factors involved in macrophage death induction.