The aim was to determine whether stronger complement activation is an early predictor of poor response to surfactant treatment in infants with severe respiratory distress syndrome (RDS). Thirty-one preterm newborns with severe RDS (initial fraction of inspired oxygen [FiO(2)] > 0.5) and 22 healthy preterm newborns were studied. The study group was divided into two subgroups according to their response to natural surfactant 6 hours after administration: good responders had reduction in FiO(2) > 50% of the presurfactant level, and poor responders had a reduction in FiO(2) <= 50%. Levels of complement 4 (C4) and C3c were measured in blood samples drawn at admission and 24 hours after birth. The poor responders to surfactant had significantly lower serum C4 levels at admission and in the first day of life than the good responders. The poor responders also had lower C3c levels at birth than the good responders, but higher C3c levels at 24 hours. Receiver-operator curve analysis revealed that, compared with C3c at admission, C4 at admission was a more sensitive and specific predictor of poor response to surfactant treatment in preterm newborns with severe RDS (area under the curve, 0.863; 95% confidence interval, 0.726 to 1; p = 0.001). Significantly decreased serum C4 at admission is a valuable early predictor of poor response prior to surfactant treatment in preterm newborns with severe PDS. C4 level may help investigators determine the mechanisms underlying poor responsiveness to surfactant.