Background: Mechanical ventilation with high tidal volumes (V-T) in contrast to mechanical ventilation with low V-T has been shown to increase plasma levels of proinflammatory and antiinflammatory mediators in patients with acute lung injury. The authors hypothesized that, in patients without previous lung Injury, a conventional potentially injurious ventilatory strategy with high V-T and zero end-expiratory pressure (ZEEP) will not cause a cytokine release into systemic circulation. Methods: A total of 39 patients with American Society of Anesthesiologists physical status I-II and without signs of systemic infection scheduled for elective surgery with general anesthesia were randomized to receive mechanical ventilation with either (1) V-T = 15 ml/kg ideal body weight on ZEEP, (2) V-T = 6 ml/kg ideal body weight on ZEEP, or (3) V-T = 6 ml/kg ideal body weight on positive end-expiratory pressure of 10 cm H2O. Plasma levels of proinflammatory and antiinflammatory mediators tumor necrosis factor, interleukin (IL)-6, IL-10, and IL-1 receptor antagonist were determined before and 1 h after the initiation of mechanical ventilation. Results: Plasma levels of all cytokines remained low in all settings. IL-6, tumor necrosis factor, and IL-1 receptor antagonist did not change significantly after 1 h of mechanical ventilation. IL-10 was below the detection limit (10 pg/ml) in 35 of 39 patients. There were no differences between groups. Conclusions Initiation of mechanical ventilation for 1 h in patients without previous lung injury caused no consistent changes in plasma levels of studied mediators. Mechanical ventilation with high V-T on ZEEP did not result in higher cytokine levels compared with lung-protective ventilatory strategies. Previous lunge damage seems to be mandatory to cause an increase in plasma cytokines after 1 h of high V-T mechanical ventilation.