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This study was designed to investigate the possible effect of injurious mechanical ventilation on peripheral immune function of healthy rats. Three ventilation strategies were compared: 1) low peak inspiratory pressure (PIP)/positive end-expiratory pressure (PEEP); 2) high PIP/PEEP; and 3) high PIP/zero PEEP (ZEEP). As a reference group, healthy, nonventilated, sham-operated, anaesthetised rats were used. After 4 h, rats were sacrificed and macrophage inflammatory protein (MIP)-2 levels in lung and plasma were determined. Peripheral immune function was determined by measurement of splenic natural killer (NK) activity, mitogen-induced splenocyte proliferation and in vitro cytokine production. All immune measurements in the low PIP/PEEP group did not differ from the immune measurements in the reference group. High PIP strategies, irrespective of applied PEEP, enhanced MIP-2 levels in lung and plasma. NK cell activity, mitogen-induced splenocyte proliferation and MIP-2 and interleukin (IL)-10 production significantly decreased after high PIP/PEEP ventilation. In the high PIP/ZEEP-ventilated group, the decrease in splenocyte proliferation, MIP-2 and IL-10 production and NK cell activity was more pronounced and interferon-gamma production was also significantly lower than in the low PIP/PEEP group. These data show that high positive inspiratory pressure ventilation induces an inflammatory response in the lung, whereas at the same time the peripheral immune response is downregulated. Ventilator-induced peripheral immune suppression may contribute to poor outcome in acute respiratory distress syndrome patients.