A pilot study of the effect of exogenous surfactant (ES) on premature infants with respiratory distress syndrome (RDS) is reported. Each of the first 15 infants in this study received 200 mg/kg of natural surfactant (Curosurf) during the first day of life. Controls were 56 infants with RDS seen in the 15 months prior to the study. Within 5 minutes of starting ES, in all infants there was rapid and dramatic improvement in oxygenation and improvement in the average arterial/alveolar ratio of 169%. They had lower oxygen and ventilatory requirements than the control group throughout the first 5 days of life. No treated infant suffered from pulmonary air leak, while in the control group 21% developed pneumothorax and 11% had pulmonary interstitial emphysema. Mortality was 13% in the treated group as compared to 27% in the control group (p less than 0.01). There were no differences between the groups in the incidence of sepsis, patent ductus arteriosus, necrotizing enterocolitis, intraventricular hemorrhage, or bronchopulmonary dysplasia, nor were there side-effects of therapy. Dosage, timing and composition of the ideal surfactant are important questions for future studies.