There are several critical differences in the pulmonary granulomatous response to Mycobacterium tuberculosis between the mouse and other animal models such as the guinea pig or rabbit. One key difference is a conspicuous lack of central caseating necrosis in pulmonary lesions of immunologically intact mice. To determine whether normal mice could develop such pathology in response to highly virulent clinical isolates of M. tuberculosis, C57BL/6 mice were infected aerogenically with varying doses of three different strains, and the development of a granulomatous response was followed for as long as a year. Whereas such conditions failed to induce caseating necrosis in the lungs of these mice, all of the infections induced a granulomatous response which progressed similarly. We present here a descriptive report of the gross pathological progression of tuberculosis in the lungs of the mice. In each case, the disease progressed in five discrete stages, which were delineated on the basis of several criteria including the extent of granulomatous involvement, the cell types present, the degree of lymphocyte organization, and the presence of destructive sequelae such as airway epithelium erosion and airway debris. Quicker progression of disease along these five stages was induced by increasing the size of the inoculum or by the more virulent mycobacterial strains. The infections with the virulent strains were not resolved, and the later stages of the granulomatous response coincided with an increasing bacillary load and a loss of organized lymphocytes in the infected lungs which ultimately resulted in the death of the host. These results indicate that although C57BL/6 mice do not manifest a caseating form of pulmonary tuberculosis, they manifest an equally pathogenic granulomatous response which appears as a chronic interstitial fibrosing response that fails to contain the infection at a time that organized lymphocyte involvement wanes in the lung.