High-tidal volume (Vt) ventilation induces lung injury and systemic inflammation, and small doses of endotoxin have been shown to increase the susceptibility to ventilation-induced lung injury. We studied whether high-Vt ventilation increases organ injury in a model of bacterial sepsis and whether an anti-inflammatory treatment averts those changes. Anesthetized rats, monitored with an arterial catheter and a blood flow probe in the aorta, were assigned to one of four different groups: nonseptic low-Vt group (Vt = 9 mL/kg, positive end-expiratory pressure = 8 cm H2O, control group), septic low-Vt group, septic overventilated group (Vt = 35 mL/kg, positive end-expiratory pressure = 0), and septic overventilated group pretreated with dexamethasone (6 mg/kg i.p., 30 min before mechanical ventilation). Rats were ventilated for 75 min. Septic rats had undergone cecal ligation and puncture 48 h before mechanical ventilation. We measured hemodynamics, lung mechanics, blood chemistry and gas exchange, liver and heart expression of cyclooxygenase 2 (COX-2) and iNOS (reverse transcriptase-polymerase chain reaction), and lung histopathology. Septic rats showed metabolic acidosis, hyperlactatemia, lung and liver injury, increased liver and heart COX-2, and liver iNOS expression. High-Vt ventilation of septic rats was associated with more marked liver injury and heart COX-2 upregulation, as well as lung inflammation and dysfunction (impaired oxygenation, increased bronchoalveolar lavage fluid protein and IL-6 concentration, decreased thoracic system compliance) and systemic hypotension. All inflammatory changes, as well as pulmonary and vascular dysfunctions, were abrogated by dexamethasone. High-Vt ventilation in bacterial sepsis upregulates the inflammatory response and aggravates the sepsis-induced cardiovascular, pulmonary, and liver dysfunction. Dexamethasone averts mechanical ventilation-induced changes under conditions of bacterial sepsis.