The local intrapulmonary role of tumor necrosis factor alpha (TNF-α) in a protective host response during acute and chronic infection with Mycobacterium tuberculosis is incompletely understood. To directly assess its role in the intrapulmonary immune response, we compared the responses of transgenic mice with a local pulmonary blockade of TNF-α (SPCTNFRIIFc mice) to mice with globally inhibited TNF-α (TNFRKO mice) and mice with normal immune systems (control mice). Consistent with previous reports, 100% of TNFRKO mice died by 28 days after aerosol infection, and these mice had markedly increased numbers of bacteria and widespread tissue necrosis in their lungs compared to controls. The median survival time of the SPCTNFRIIFc mice was 142 days, and 75% died by 180 days. Even though the numbers of bacteria in the lungs of the SPCTNFRIIFc mice were marginally increased compared to controls, these mice had a persistent neutrophilic inflammatory response and increased expression of proinflammatory cytokines (interleukin-1α/β [IL-1α/β], IL-18, gamma interferon, IL-6, and macrophage migration inhibitory factor) and chemokines (eotaxin, macrophage inflammatory protein 1α/β, gamma interferon-inducible protein 10, macrophage chemotaxic protein 1, and TCA-3) in their lungs. These studies with the SPCTNFRIIFc mice provide direct evidence for the local importance of TNF-α in the proper regulation of host defense to M. tuberculosis. The studies also suggest that when the local actions of TNF-α are selectively impaired in the lungs, tissue destruction and death ensue, at least in part, due to persistent expression of proinflammatory mediators that would normally be downregulated.