We report that BPI-deficient mice exhibit decreased ability to limit P. aeruginosa infection in both the lung and peritoneum in vivo. Thus, in this model system, BPI plays a functionally non-redundant role in innate immunity against P. aeruginosa. This defect is characterized by increased neutrophil accumulation and production of inflammatory cytokines at sites of infection, propagated by increased recruitment of neutrophils from the bone marrow in Bpi-/- mice. Here, BPI is linked to infection.