Mechanical nonuniformity of diseased lungs may predispose them to ventilator-induced lung injury (VILI) by overinflation of the more compliant, aerated zones. Perfluorocarbon (PFC) may reduce this nonuniformity by suppressing air-liquid interfaces. Saline (6.8 ml/kg) was instilled into the trachea to mimic alveolar edema and reduce aerated lung volume before mechanical ventilation (6, 16, 24, or 32 ml/kg tidal volume [VT]) for 10 min in rats. Flooding significantly aggravated VILI when VT was 24 or 32 ml/kg, with an increase in the distribution space of albumin in lungs (p < 0.001). Tracheal instillation of a low dose (3.3 ml/kg) of PFC (Liquivent) either before or after the instillation of saline considerably reduced VILI (p < 0.001). Saline instillation raised the lower inflection point of the respiratory system pressure-volume curve to values as high as 25 cm H2O, and produced a significant increase in end-inspiratory pressure (from 38 +/- 2.0 cm H2O to 61 +/- 2.4 cm H2O, for a VT of 32 ml/kg; p < 0.001). PFC significantly reduced the pressure at the lower inflection point and normalized end-inspiratory pressure. These decreases were correlated with a smaller albumin distribution space (p < 0.001). Animals in which PFC instillation failed to reduce the albumin space had pressures similar to those of animals given saline alone. In conclusion, the effectiveness of PFC instillation in reducing VILI may be predicted by the shape of the pressure-volume curve. These findings may help in designing safer clinical studies of mechanical ventilation and in reducing the cost of partial liquid ventilation by reducing doses of PFC.