The effect of various perflubron doses on overdistension lung injury was evaluated. Rats were given perflubron at 0 ml/kg (control) to 20 ml/kg and ventilated with a VT of 33 ml/kg without or with 5 cm H2O of positive end-expiratory pressure (PEEP). High (20 ml/kg), but not lower, perflubron doses aggravated lung capillary leak in the absence of PEEP. PEEP application aggravated capillary leak in controls, had no effect in those given a low (10 ml/kg) dose, but decreased the leak in rats ventilated with a large dose compared with zero end-expiratory pressure. In the presence of PEEP, this low dose decreased capillary leak compared with controls or with rats given the large dose. Lung computerized tomography scans showed that the large dose increased functional residual capacity by 68% and produced gas trapping that was reduced by PEEP. Thus, large doses predispose to overdistension injury whereas low doses do not and may even have a protective effect in the presence of PEEP. The paradoxical beneficial effect of PEEP when large doses are given may be due to gas trapping reduction. These findings confirm that liquid ventilation does not aggravate volutrauma provided perflubron doses are adjusted. They provide a lead to further investigate partial liquid ventilation in the clinical setting.