MAST cells play a detrimental role in IgE-dependent allergic reactions. In contrast, a protective function for mast cells has been proposed on the basis of some worm infection models. No reports exist on the in vivo significance of these cells in bacterial infections^1,2. Here we use congenitally mast-cell-deficient W/W^v mice and normal +/+ littermates^3,4 to analyse the role of mast cells in a model of acute septic peritonitis (caecum ligation and puncture (CLP)). Following CLP, W/W^v mice showed a significantly increased mortality compared to +/+ mice. The selective reconstitution of W/W^v mice with cultured +/+ mast cells substantially protected them from the lethal effects of CLP, whereas an anti-tumour-necrosis-factor (TNF) antibody injected immediately after CLP completely suppressed this protection. Our results reveal a previously unrecognized protective role of mast cells and mast-cell-derived TNF in acute bacterial peritonitis.