In vitro data have shown a concentration-dependent inhibition of surfactant by meconium, while anecdotal reports demonstrate improved oxygenation after surfactant replacement in babies with meconium aspiration syndrome, particularly in conjunction with high-frequency jet ventilation. We randomized 70 newborn piglets to either conventional or high-frequency jet ventilation, followed by insufflation of 3 mL/kg of a 33% meconium solution. Each group was further randomized to one of five surfactant therapies: 1) control, 2) 4 mL/kg Survanta, 3) 8 mL/kg Survanta, 4) 5 mL/kg Exosurf, or 5) 10 mL/kg Exosurf. We followed arterial blood gases and ventilator requirements over 6 h of ventilation. Aspirates of airway fluids were obtained for surface tension measurements, as well as total protein and phospholipid concentrations. Using a previously established scoring system, a pathologist blinded to treatment evaluated four sections of lung per animal for histologic changes of meconium aspiration syndrome. There were no differences noted between groups in any physiologic parameter measured (mean airway pressure, arterial partial pressure of oxygen/alveolar partial pressure of oxygen ratio, etc.) during the 6 h of ventilation. Airway fluid aspirate total protein concentrations increased significantly after meconium instillation (4- to 5-fold, p < 0.007) and remained elevated in spite of surfactant therapy. There was an initial decline in airway phospholipid concentrations after meconium instillation followed by a rise to levels equal to or greater than premeconium levels. Surface tension measurements increased in all groups after meconium insufflation (p < 0.012) and did not decline thereafter, despite standard and twice-standard surfactant doses of both types.(ABSTRACT TRUNCATED AT 250 WORDS)