A family of G-protein-coupled chemoattractant receptors is known to mediate the transport and activation of neutrophils and macrophages This family includes receptors for chemokines, such as interleukin-8, bacterial formylated peptides, platelet-activating factor, leukotriene B4, and the complement anaphylatoxins. The apparent redundancy of these receptors suggests that they have an important underlying role in host defence. To isolate the contribution of particular molecules, we disrupted a gene that encodes a single chemoattractant receptor. Here we show that mice deficient in the chemoattractant C5a receptor, in comparison to their wild-type littermates, were unable to clear intrapulmonary-instilled Pseudomonas aeruginosa, despite a marked increase in neutrophil influx, and succumbed to pneumonia. These C5a-receptor-deficient mice challenged with sublethal inocula of Pseudomonas become superinfected with secondary bacterial strains. We conclude that the C5a receptor has a non-redundant function, and is required for mucosal host defence in the lung.