ALTHOUGH mast cells have been implicated in a variety of inflammatory conditions including immediate hypersensitivity and interstitial cystitis,(1,2) their physiological role in the body is unknown. We investigated the role of mast cells in host defence against bacterial infections using a well characterized mast-cell-deficiency mouse model(3,4). We report here that mast cells, which are selectively located at portals of bacterial entry, are important to host defence. Mast-cell-deficient WBB6F1-W/W-v mice (W/W-v) were up to 20-fold less efficient in clearing enterobacteria than WBB6F1+/+ (+/+)mice or mast-cell-reconstituted W/W-v (W/W-v + MC) mice. With higher bacterial inocula, only W/W-v mice died (80%). The limited bacterial clearance in W/W-v mice directly correlated with impaired neutrophil influx. The mast-cell chemoattractant TNF-alpha was implicated in the neutrophil response because TNF-alpha was locally released only in +/+ and W/W-v + MC mice, TNF-alpha-specific antibodies blocked over 70% of the neutrophil influx, and purified mast cells released TNF-alpha upon incubation with bacteria. Additionally, the type-1 fimbrial subunit, FimH, was the necessary enterobacterial component for mast-cell activation and neutrophil influx because an isogenic FimH(-) mutant evoked a limited neutrophil response in +/+ mice compared to wild-type bacteria.