Pseudomonas aeruginosa is a major cause of nosocomal and community acquired chronic infections in subjects with compromised respiratory function. The microbe is environmentally ubiquitious and has a high level of innate antimicrobial resistance. This has led researchers to investigate vaccine and immunotherapeutic approaches to prevent and treat P. aeruginosa infections. Seven cytosolic non-integral proteins were studied as vaccine candidates in an acute lung infection model in the rat. Five of these (amidase, amidopeptidase, KatE, KatE and Pa13 a novel 13 kDa protein) enhanced bacterial clearance from the lung compared to control animals following challenge and are worthy of further study. Immune mechanisms stimulated by these proteins in response to both immunization and infection varied. The most pronounced degree of bacterial clearance from the lung was associated with antigens, which demonstrated greater surface exposure and induced an increase in phagocyte recruitment, in particular, an increased proportion of polymorphonuclear leukocytes. Lymphocytic proliferation and specific antibody responses in the absence of enhanced clearance were less informative as immune correlates.