Objective. To evaluate the effects of protective and conventional ventilation with or without positive end-expiratory pressure (PEEP), on systemic tumor necrosis factor-alpha, interleukin-6 levels and pulmonary function during open heart surgery. Design. Prospective, randomized clinical study. Setting. Single university hospital. Patients and participants. Forty-four patients undergoing elective coronary artery bypass grafting surgery with cardiopulmonary bypass. Interventions. Patients ventilated with (1) protective tidal volumes (6 ml/kg, respiratory rate: 15 breaths/min, PEEP 5 cmH(2)O, n=15) group PV; (2) conventional tidal volumes (10 ml/kg, respiratory rate: 9 breaths/min, PEEP 5 cmH(2)O, n=14) group CV+PEEP and (3) conventional tidal volumes (10 ml/kg, respiratory rate: 9 breaths/min, n=15) without PEEP, group CV+ZEEP. Various pulmonary parameters, systemic TNF-alpha and IL-6 levels were determined throughout the study. Measurements and results. There were no differences among the groups regarding the systemic TNF- alpha and IL-6 levels. The plateau airway pressures of group PV were lower than those of groups CV+PEEP (p=0.02) and CV+ZEEP (p=0.001) after cardiopulmonary bypass. The shunt fraction of group PV was significantly lower than that of group CV+ZEEP 24 h after surgery (p<0.05). Oxygenation and the alveolar-arterial oxygen difference were better in both PEEP groups than in group CV+ZEEP 24 h after the operation. Conclusions. We could not find any evidence that protective mechanical ventilation prevents some of the adverse effects of cardiopulmonary bypass on the lung, nor systemic cytokine levels, postoperative pulmonary function or length of hospitalization.