Administering surfactant during pediatric extracorporeal membrane oxygenation (ECMO) may influence important clinical variables but has been insufficiently described. Ninety-six courses of ECMO from our center were retrospectively assessed, and 89 surfactant doses were identified during 37 ECMO courses. Surfactant administration was associated with a respiratory indication for ECMO and increased durations of ECMO and positive pressure ventilation. Hospital survival was 64.9% (24) in surfactant-treated ECMO courses and 72.9% (43) otherwise (p = 0.41). Dynamic compliance of the respiratory system (Cdyn; shown as least squares mean [standard error] in ml/cm H2O/kg by mixed-effects modeling) increased significantly from 0.34 (0.03) before surfactant to 0.40 (0.03) within 12 hours (p = 0.023) and to 0.45 (0.03) within 24 hours (p < 0.001) of surfactant administration. Other mechanical ventilator parameters, ECMO settings, and arterial blood gas results did not differ significantly after surfactant administration. Among surfactant recipients, significantly increased Cdyn was observed in the nonsurgical group (n = 20) but not in the cardiac surgery group (n = 17). In conclusion, respiratory system compliance is increased after surfactant administration and noncardiac surgical patients may preferentially benefit from this therapy. Surfactant administration was associated with longer durations of mechanical support, but not with unfavorable mortality.