Understanding the immunological mechanismsof protection and pathogenesis in tuberculosis remains problematic. We have examined the extent to which tumor necrosis factor-u (TNFu) contributes to this disease using murine models in which the actlon of TNFa is inhibited. TNFa was neutralized in vlvo by monoclonal antibody; in addition, a mouse strain with a disruption in the gene for the 55 kDa TNF receptor was used. The data from both models established that TNFa and the 55 kDa TNF receptor are essential for protection against tuberculosis in mice, and for reactive nitrogen production by macrophages early in infection. Granulomas were formed in equal numbers in control and experimental mice, but necrosis was observed only in mice deficient in TNFa or TNF receptor. TNFa and the 55 kDa TNF receptor are necessary conditions for protection against murine M. fuberculosis infection, but are not solely responsible for the tissue damage observed.