The therapeutic efficacy of dexamethasone and a natural pig surfactant preparation was investigated in a rabbit aspiration model. Lung injury was induced by intratracheal administration of 2 mL of a betaine hydrochloride-pepsin mixture per kilogram body weight (BW). Dexamethasone (n = 34) was given intravenously in two doses (D1 = 7.5 mg/kg BW; D2 = 3.75 mg/kg BW; D2 6 h post D1). In different groups D1 was injected at different times (T = -2, 0, +2, and +24 h) before and after aspiration. Natural surfactant (n = 5) was administered 24 h post lung injury in a single dose of 12 mg phospholipids per kilogram body weight. The therapeutic potential was evaluated by measuring static lung compliance and the difference in a lung volume between 0 and 20 mm Hg airway pressure. No therapeutic effect of dexamethasone was seen at any time of application. In contrast, the intratracheal administration of natural surfactant 24 h post injury completely reversed the deterioration of lung mechanic properties.