The ability of (Mtb) to persist in its host is central to the pathogenesis of tuberculosis, yet the underlying mechanisms remain incompletely defined. PerM, an integral membrane protein, is required for persistence of Mtb in mice. Here, we show that deletion caused a cell division defect specifically during the chronic phase of mouse infection, but did not affect Mtb's cell replication during acute infection. We further demonstrate that PerM is required for cell division in chronically infected mice and in vitro under host-relevant stresses because it is part of the mycobacterial divisome and stabilizes the essential divisome protein FtsB. These data highlight the importance of sustained cell division for Mtb persistence, define condition-specific requirements for cell division and reveal that survival of Mtb during chronic infection depends on a persistence divisome.