We investigated the effects of lung edema protein on ventilatory mechanics with special reference to surfactant activity. The edema fluid was obtained from hyperoxia-exposed adult rabbits. In immature newborn rabbits that could not be artificially ventilated at an insufflation pressure of 25 cm H2O, mean tidal volumes of > 27 ml/kg were obtained by supplementation with a natural surfactant (S-alone) or natural surfactant mixed with lung edema fluid (EF), the edema protein-to-surfactant ratio of which was < or = 5.6. A mixture with a ratio of 11.2 (11.2-EF/S), however, decreased the volume to 10.9 ml/kg (P < 0.05 vs S-alone). Surfactant mixed with isolated albumin at a concentration equal to that in 11.2-EF/S decreased the tidal volume to 8.6 ml/kg (NS vs 11.2-EF/S), and with isolated fibrinogen lowered it to 18.1 mg/kg (P < 0.05 vs S-alone). We conclude that lung edema fluid impairs ventilation through surfactant inactivation when the protein-to-surfactant ratio increases, and that albumin and fibrinogen are the main causes of this impairment.