Most studies of mast cells have been directed at their role in the pathophysiology of IgE-mediated allergic reactions with little recognition of their participation in bacterial infections. We report that mast cells can specifically bind FimH, a mannose-binding subunit on type 1 fimbriae expressed by Escherichia coli and other enterobacteria. This interaction triggers mast cell phagocytosis and killing of the bacteria within vacuoles and through the release of superoxide anions. Also, in view of the fact that mast cells have the capacity to release inflammatory mediators and are particularly abundant in the skin, mucosal surfaces, and around blood vessels, we suggest that these cells play an important role in host defense against microbial infection.