Mycobacterium tuberculosis comes in contact with pulmonary surfactant, alveolar macrophages and type II epithelial cells. Alveolar type II epithelial cells secrete pulmonary surfactant, a complex mixture of phospholipids and proteins lining the alveolar surface, while alveolar macrophages are involved in surfactant catabolism. Surfactant proteins SP-A and SP-D modulate phagocytosis of M. tuberculosis by alveolar macrophages. We have reported that mice with decreased surfactant catabolism resulting from GM-CSF deficiency are highly susceptible to acute aerosol infection with 100 cfu of M. tuberculosis. Here, we evaluated the lungs of WT, GM-CSF-deficient, and GM-CSF-corrected mice surviving six months after sub-acute aerosol infection of 5-10 cfu M. tuberculosis. We show that GM-CSF-deficient mice develop intra-bronchial and intra-alveolar tuberculosis lesions with numerous mycobacteria, inflammatory cells, and extracellular proteinaceous material containing surfactant protein B (SP-B). In contrast, WT and GM-CSF-corrected mice develop typical epithelioid granulomas containing lymphocytes, SP-B positive cells, and M. tuberculosis bacilli inside macrophages. Our findings support the concept that whole pulmonary surfactant is an important component of host mycobacterial infection in the distal lung.