BACKGROUND: Monocyte deactivation, defined as the decrease of surface expression of class II molecules of the main histocompatibility complex (MHC) on circulating monocytes, can occur after severe injuries, like trauma, sepsis, or major surgery. We hypothesized that mechanical ventilation could also be a cause. METHODS: Prospective experimental study. Intact and endotoxin-treated (20 mg/kg of intraperitoneal lipopolysaccharide, 4 hours before the experiment) Swiss mice were tracheotomized and ventilated with one of four possible ventilatory settings: control (no ventilation), low pressure (peak pressure 20 cm H2O, positive end-expiratory pressure [PEEP] 4 cm H2O), high pressure (peak pressure 30 cm H2O, PEEP 0 cm H2O), or high pressure plus an intraperitoneal dose of interferon (IFN)-gamma (40,000 units). After 1 hour, an arterial blood sample was obtained, and the right lung removed to measure gas exchange and the lung wet-to-dry weight ratio. Expression of class II MHC molecules was assessed in peripheral monocytes using flow cytometry. RESULTS: High-pressure ventilation was related to a decrease in oxygenation and to an increase in lung wet-to-dry weight ratio. The expression of class II MHC molecules in blood monocytes decreased in the high-pressure group, but not in IFN-gamma-treated mice. The results were similar in both intact and endotoxin-treated mice. CONCLUSIONS: Mechanical ventilation with high pressure and zero PEEP can cause monocyte deactivation. This phenomenon can be avoided by treatment with IFN-gamma.