In order to evaluate the role of pulmonary surfactant in the prevention of lung injury caused by mechanical ventilation (MV) at low end-expiratory volumes, lung mechanics and morphometry were assessed in three groups of 8 normal, open-chest rabbits ventilated for 3-4 h at zero end-expiratory pressure (ZEEP) with physiologic tidal volumes (V_T=10 ml^.kg^-1). One group was left untreated (group A), the other two received surfactant intratracheally (group B) or aerosolized dioctylsodiumsulfosuccinate (group C) before MV on ZEEP. Relative to initial MV on PEEP (2.3 cmH₂O), quasi-static elastance (Est) and airway (Rint) and viscoelastic resistance (Rvisc) increased on ZEEP in all groups. After restoration of PEEP, only Rint (124%) remained elevated in group A, only Est (36%) was significantly increased in group B, whereas in group C Est, Rint and Rvisc were all markedly augmented (274, 253, and 343%). In contrast, prolonged MV on PEEP had no effect on lung mechanics of 8 open-chest rabbits (group D). Lung edema developed in group C (wet-to-dry ratio=7.1), but not in the other groups. Relative to group D, both group A and C but not B, showed histological indices of bronchiolar injury, while all groups exhibited an increased number of polymorphonuclear leukocytes in alveolar septa, which was significantly greater in group C. In conclusion, administration of exogenous surfactant largely prevents the histological and functional damage of prolonged MV at low lung volumes, whereas surfactant dysfunction worsen the functional alterations, also because of edema formation and, possibly, increased inflammatory response.