The chronic phase of Mycobacterium tuberculosis infection in mouse experimental models is characterized by the accumulation of foamy macrophages (FM) – which shape the outer ring of the granuloma – in the alveolar spaces, as detected in paraffin-embedded tissues stained with hematoxylin–eosin. In this study, the use of semi- and ultra-thin sections offers more detailed information about the origin of FM both in mouse and guinea-pig experimental models. Lipid bodies (LB) are present in macrophages from the beginning of infection and accumulate in the chronic phase. LB progress from an early (ELB) to a late (LLB) stage, defined according to their progressive capacity to generate cholesterol crystals, resembling atherosclerotic lesions. FM arise from massive accumulation of LLB. Electronic microscopy reveals intracellular lipophilic inclusions (ILIs) in those M. tuberculosis bacilli inside FM. It is our hypothesis that the accumulation of lipids in M. tuberculosis concomitant to the establishment of the non-replicating state prepares the bacilli for future reactivation and for facing future stressful environments.