The aim of this study was to determine whether the effects of alveolar distention and surfactant dysfunction on alveolocapillary barrier function are different and additive. Pulmonary clearance of aerosolized technetium-99m-labelled human serum albumin (99mTc-HSA) was used to characterize barrier function after perturbing the surfactant system with the detergent dioctyl sodium sulphosuccinate either singly or in combination with large tidal volume ventilation (LTVV). Clearance was measured for 3 h (Experimental ventilation) in four groups (n = 6 each) of rabbits: 1) Controls; 2) Detergent; 3) LTVV; and 4) Detergent + LTVV. Restoration of clearance (Recovery) was studied for 3 h under conventional ventilation. The half-life of clearance (t 1/2) decreased during LTVV (305 min) compared to 1,055 min in Controls. Detergent induced a biexponential clearance with slow (t 1/2S) and fast (t 1/2F) half-lives of 670 and 15.4 min, respectively. The fast fraction (fF) was 0.20. Clearance in the Detergent + LTVV group was also biexponential. The t 1/2F and fF were similar to the Detergent group. The t 1/2S was similar to the LTVV group. The fF in this group increased to 0.36 during Recovery (p < 0.01 versus Detergent group and p < 0.05 versus Experimental ventilation). The diverse kinetics of clearance during large tidal volume ventilation and surfactant dysfunction suggest the presence of different mechanisms affecting the barrier. The mechanisms have additive characteristics, which superimpose to produce lung injury.