Surfactant can be inhibited in vivo by plasma proteins invading the alveolar space during acute lung injury. We tested the resistence of surfactant preparations with synthetic peptides against inhibition by human albumin in preterm rabbits. Surfactant preparations studied included a standard phospholipid mixture (PL), PL with 3% surfactant peptide B1-78(B), PL with 3% surfactnat peptide B1-78 and 1% palmitoylated surfactant peptide C1-35 (BC), PL with 3% KL4 peptide(KL4), and Survanta®. Preterm rabbits born at 28 d gestation were intubated and placed in a temperature-controlled ventilator-plethysmography system with 100% oxygen and a positive end-expiratory pressure of 3 cm H2O. Peak inspiratory pressure was adjusted individually to achieve tidal volumes of 6-7 ml/kg as measured with a pneumotachometer. Rabbits received 100 mg of human albumin intratracheally at 30 min, followed by 100 mg/kg of surfactant at 45 min, and were killed and lavaged at 105 min. Groups consisted of 5-8 animals. Mean dynamic compliance decreased from 0.56 to 0.40 ml/kg/cm H2O after albumin instillation. Sixty min after surfactant treatment, dynamic compliance was 82% of the post-albumin values in rabbits treated with BC, 63% with Survanta, 59% with KL4, 53% with B, and 48% with PL. Protein content of the lung lavages was lowest after BC, intermediate after KL4, B, and PL, and highest after Survanta treatment. These data suggest that a combination of synthetic surfactant peptides B and C confers a high degree of resistence against surfactant inhibition by human albumin in ventilated preterm rabbits.