A blinded, randomized, controlled study was designed to test whether multiple-dose surfactant therapy would improve pulmonary outcome in term infants with respiratory failure, resulting in a shortened period of extracorporeal membrane oxygenation (ECMO). Infants > or = 34 weeks of gestational age in severe respiratory failure and receiving ECMO were stratified by diagnosis and then randomly assigned to the treatment or the control group. Four doses of modified bovine lung surfactant extract (beractant) were administered to the surfactant group (n = 28), and an equal volume of air was administered to the control group (n = 28). Lung compliance was initially low in both groups; after treatment, values were higher with time in the surfactant group (F = 5.40, p = 0.026). The ECMO treatment period was significantly shorter in the surfactant group (mean +/- SD: 107 +/- 33 hours vs 139 +/- 54 hours for the control group; U = 232, p = 0.023). Tracheal aspirate concentrations of surfactant protein A were low in both groups, and then increased steadily to a higher level in the surfactant group (F = 2.58, p = 0.04). The overall incidence of complications after ECMO was decreased in the surfactant group (18% vs 46% for the control group; chi-square value = 5.004, p = 0.025). Radiographic scores, echocardiographic findings, incidence of intracranial or pulmonary hemorrhage and bronchopulmonary dysplasia, time to extubation, duration of oxygen therapy, and duration of hospitalization did not differ between the two groups. Beractant in this population improved pulmonary mechanics, increased surfactant protein A content in tracheal aspirate, decreased time on ECMO duration, and reduced disease complications.