Neutrophils have been shown to be important in the clearance of Pseudomonas aeruginosa from murine lungs. The mechanisms responsible for the neutrophil influx into the lungs, however, remain poorly defined. This study was undertaken to define the contribution to this inflammatory process by the C5 molecule or its fragments. Congenic C5 sufficient (B10.D2/nSn) and CS deficient (B10.D2/oSn) mice were challenged by intrapulmonary administration of Pseudomonas aeruginosa. Differences in survival of the 2 strains of mice were noted over a 6-day period. In addition, host response was assessed at 6-, 24-, and 48-h time points by histologic examination, analysis of cells from pulmonary lavage, analysis of cells in the peripheral blood and culture of the lungs and blood of challenged mice. Mortality was consistently higher in C5 deficient mice. Neutrophil accumulation within the lung was greater at the 6-h time point in the C5 sufficient mice, and greater at the 48-h time point in the C5 deficient mice as demonstrated by both lavage and histologic examination. Differences in neutrophil accumulation could not be explained by differing blood neutrophils concentrations in the mice before challenge, or a lack of mobilization of neutrophils into the peripheral circulation after challenge in the C5 deficient mice. An early lack of clearance of the bacteria from the lungs of the C5 deficient strain was documented. We conclude that the C5 molecule and its phlogistic fragments are important neutrophil chemotaxins in murine lungs exposed to Pseudomonas aeruginosa, and, quantitatively, may be the most important early stimulus for neutrophil accumulation in this model.