Introduction: Natural surfactants have been shown to be superior to synthetic surfactants in the treatment of neonatal respiratory distress syndrome (RDS). In Germany, Alveofact^® (A) and Curosurf^® (C) are the most frequently used natural surfactant preparations. The aim of this retrospective, observational study was to compare the effects of A and C on gas exchange and outcome in premature infants. Methods: During a 5-year period in our neonatal intensive care unit (NICU), 187 premature infants were treated with surfactant, with 82 receiving A and 105 receiving C. We recorded F_IO₂ and gas exchange (PaO₂/F_IO₂ ratio, PaCO₂, SaO₂) during the first 72 h after surfactant application and the incidence of outcome parameters at day 28 (bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH grade III or IV), patent ductus arteriosus (PDA), pneumothorax, necrotizing enterocolites (NEC) and death). The differences between the patient groups were assessed by ANOVA or the calculation of relative risks. Bonferroni correction was used for multiple comparisons. Results: There were no statistically significant differences between infants treated with A and C in mean gestational age (28.4 vs. 28.4 weeks), birth weight (1210 vs.1258 g) and time of first surfactant application (60 vs. 90 min postnatal). We observed no significant between group differences in course of F_IO₂ and blood gases, or in incidence at day 28 of BPD (41.7% vs. 42.8%), IVH III/IV (18.3% vs. 14.3%), pneumothorax (9.8% vs. 4.8%), PDA (23.2% vs. 21.9%), PVL (7.3% vs. 9.5%) and death (17% vs. 17.1%). There were also no statistically significant differences in the subgroup of infants <28 weeks. The lower incidence of NEC in A compared with C (1.2% vs. 10.5%, P = 0.01) was not statistically significant after Bonferroni correction. Conclusion: Independent of gestational age no significant difference in the clinical efficacy of A and C was observed.