Changes in interstitial pulmonary pressure (Pip) are thought to be crucial for clearance of alveolar fluid soon after birth, although prematurity may alter these events. Therefore we hypothesized that exogenous surfactant, other than reducing atelectasis, would also determine changes in Pip. To verify this hypothesis preterm rabbits (28-30 days gestation, body weight 21.5-47.3 grams) were studied. They were delivered by cesarean section, and after intratracheal instillation of natural porcine surfactant (Curosurf) were allowed to breathe spontaneously. Pip was measured from 1 to 6 hours postnatal age (after paralysis) by micropuncture through a pleural window under direct vision. Premature lungs had structural dishomogeneity, exhibiting expanded, over expanded and atelectatic regions. Measurements of Pip indicated that there was very high dishomogeneity during the first two hours of life, such that Pip varied from subatmospheric in less expanded regions to +4 cm H2O in well aerated regions. In these expanded areas behavior of Pip followed the pattern seen in term animals, with a decrease to slightly sub atmospheric values from the 3rd hour of life. In contrast, in surfactant untreated preterm rabbits Pip remained clearly positive for up to 6 hours indicating impaired removal of fluid from the interstitial matrix. Wet to dry ratio of the lung was lower in surfactant treated than in untreated premature rabbits(5.7±0.4 vs 8.4±0.7, mean±SD) despite similar plasma protein concentration (2.96±0.8 vs 3.1±0.3 g/dl) and colloid osmotic pressure (13.7±0.6 vs 14.3±0.8 mmHg), confirming faster lung fluid clearance in treated rabbits. Our results indicate: 1) inhomogeneous distribution of surfactant leads to inhomogeneous distribution of Pip; 2) surfactant induced lung expansion is associated with enhanced lung fluid clearance. We speculate that this effect is related to alveolar distension with resultant alteration in hydration state of the interstitial matrix.