TNF is produced in the spleens of Listeria-infected mice during the first 3 days of a sublethal immunizing infection. The production of Listeria-induced TNF coincides with the time when peak numbers of bacteria are present in the liver and spleen. Evidence suggesting that TNF produced in Listeria-infected organs functions in a T cell-independent resistance mechanism comes from results showing that listeriosis is exacerbated in both T cell-intact mice and T cell-deficient (athymic nude) mice treated with a monospecific anti-murine TNF IgG. Listeriosis is exacerbated, however, only if the anti-TNF IgG is given during the first 3 days of infection, i.e., at the time when TNF is being produced in the spleen. Anti-TNF IgG administered on the first day of infection neutralized all the cytotoxic activity of endogenously produced TNF in the spleen. Additional evidence that TNF plays an important role in antibacterial defenses was obtained by showing that administration of pure murine rTNF protects mice against a normally lethal Listeria challenge given 1 to 24 h later.