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Mechanical ventilation with high tidal volumes (VT) and zero or low positive end-expiratory pressure increased mediator release to inflammatory stimuli or acute lung injury. We studied whether mechanical ventilation modifies the inflammatory responses during major thoracic or abdominal surgery. Sixty-four patients undergoing elective thoracotomy (n = 34) or laparotomy (n = 30) were randomized to receive either mechanical ventilation with VT = 12 or 15 mL/kg ideal body weight, respectively, and zero end-expiratory pressure, or VT = 6 mL/kg ideal body weight with positive end-expiratory pressure of 10 cm H2O. In 62 patients who completed the study, arterial oxygena- tion was not different between groups. Tumor necrosis factor, interleukin (IL)-1, IL-6, IL-8, IL-10, and IL-12 were determined by cytometric bead array in plasma after 0, 1, 2, and 3 h and in tracheal aspirates after 3 h of mechanical ventilation. Data were log-transformed and analyzed using parametric or nonparametric tests, as indicated. All plasma mediators increased more during abdominal than during thoracic surgery, although the differences were small. However, neither time course nor concentrations of pulmonary or systemic mediators differed between the two ventilatory settings. Our data suggest that the ventilatory settings we studied do not affect inflammatory reactions during major surgery within 3 h.