Pneumonia caused by Pseudomonas aeruginosa carries a high rate of morbidity and mortality. A lung-protective strategy using low tidal volume (V_T) ventilation for acute lung injury improves patient outcomes. The goal of the present study was to determine whether low V_T ventilation has similar utility in the setting of severe Pseudomonas aeruginosa infection. A cytotoxic Pseudomonas aeruginosa strain, PA103, was instilled into the left lung of rats anesthetized with pentobarbital. The lung-protective effect of low V_T (6 ml/kg) with or without high PEEP (10 or 3 cm H₂O) was then compared with high V_T with low PEEP ventilation (V_T 12 ml/kg, PEEP 3 cm H₂O). Severe lung injury and septic shock was induced. While ventilatory mode had little effect on the involved lung or septic physiology, injury to non-involved regions was attenuated by low V_T ventilation as indicated by the wet to dry weight ratio (W/D) (6.13±0.78 vs. 3.78±0.26, respectively) and confirmed by histopathological examinations. High PEEP did not yield significant protective effect (W/D: 4.03±0.32), but rather caused overdistension of non-involved lungs. Broncho-alveolar lavage revealed higher concentrations of TNF- in the fluid of noninvolved lung undergoing high V_T ventilation when compared to those animals receiving low V_T. We conclude that low V_T ventilation is protective in non-involved regions and that the application of high PEEP attenuated the beneficial effects of low V_T ventilation, at least in the short-term. Further, low V_T ventilation cannot protect the involved lung, and high PEEP did not significant alter lung injury over a short time-course.