Leakage of proteins into the alveolar space due to increased endothelial and epithelial permeability can inhibit pulmonary surfactant function and may worsen respiratory failure in newborn infants. We tested the effect of intratracheal instillation of fetal calf serum (FCS) and fresh frozen plasma(FFP) on lung function in surfactant-deficient rats. Eight groups of 7 rats were ventilated with 100% oxygen, a tidal volume of 7.5 ml/kg, and a rate of 60/min, and lavaged with saline until the PaO2 dropped below 100 torr. Post-lavage, the rats were treated with 100 mg/kg of Survanta (Surv), Survanta+ 2 doses of 10 ml/kg of FCS or FFP at 60 and 75 min (Surv60/FCS×2 or Surv60/FFP×2), 2 doses of FCS or FFP at 0 and 15 min (FCS×2 or FFP×2), air placebo (NT), or NT + 2 doses of FCS or FFP at 60 and 75 min(NT60/FCS×2 or NT60/FFP×2). After 105 min of ventilation, pressure volume curves were performed, and the lungs were re-lavaged. FCS instillation rapidly improved oxygenation when given immediately post-lavage (FCS×2) or 60 min after an air placebo (NT60/FCS×2) or Survanta(Surv60/FCS×2). In contrast, FFP instillation did not affect oxygenation when given immediately post-lavage (FFP×2) or 60 min after air placebo(NT60/FFP×2), but reduced oxygenation when given 60 min after Survanta instillation (Surv60/FFP×2). Both FCS and FFP had a strong negative effect on lung volume in the pressure-volume curves. Mean protein content in the final lavages in all groups of rats treated with FCS or FFP was higher than after surfactant treatment only. Surfactant aggregate sizing of the final lung lavages by dynamic light scattering showed a definite shift towards smaller aggregates after FFP, but not after FCS instillation. We conclude that intratracheal instillation of FCS improves oxygenation and preserves the presence of large surfactant aggregates in surfactant-deficient and surfactant-treated lavaged rats, whereas FFP decreases oxygenation and the average surfactant aggregate size in surfactant-treated lavaged rats.