BACKGROUND The respiratory distress syndrome (RDS) in premature newborns has been etiologically correlated to immature lungs and specifically with surfactant deficiency. Exogenous administration of surfactant is nowadays considered to be the treatment of choice. In this paper we attempt a comparison of clinical results from the administration of natural Alveofact and synthetic Exosurf surfactants in premature newborns with respiratory distress syndrome. METHODS The study subjects were 92 premature newborns who had been hospitalized in the Department of Neonatology, of the University of Crete. A total of 42 subjects received synthetic surfactant and 50 subjects received natural surfactant. The surfactant was administered in one to three doses, depending on respiratory support requirements. RESULTS The time of administration was a little longer for the natural surfactant group. The duration of mechanical ventilatory support, requiring oxygen, the duration of hospitalization and the percentage of increase of arterial alveolar partial pressure oxygen ratio (a/APO2) were slightly higher for the synthetic surfactant group. The mortality rate during the neonatal period (28th day) was higher for the synthetic surfactant group than for the natural surfactant group (38.1 vs 24%). A similar tendency was noticed also as regards to complications, e.g. pneumothorax (11.2 vs 5.2%; relative risk (RR) 0.27) intraventricular hemorrhage (34.6 vs 21.1%; RR 0.61), septicemia (11.5 vs 5.2%; RR 0.46) and bronchopulmonary dysplasia (12.5 vs 2.8%; RR 0.22). CONCLUSION The use of natural surfactant seems to offer more advantages in comparison with its synthetic counterpart.