Twenty-nine children 3 months to 17 years of age undergoing operations for congenital heart disease were included in this prospective study. Complement activation, activation of the plasma contact system, leukocytes, leukocyte elastase release, and C-reactive protein were studied during and after cardiopulmonary bypass for the first postoperative week and related to multiple system organ failure occurring in eight (27.5%) of the 29 children. During cardiopulmonary bypass complement activation via the alternative pathway as indicated by significant conversion of C3 (expressed by C3d/C3) and abnormally high C5a values at the end of cardiopulmonary bypass without consumption of C4 was shown in all children. At the end of cardiopulmonary bypass, C3 conversion was significantly higher in the eight patients with multiple system organ failure than in the others (p < 0.05), whereas no difference in C5a level was shown. All children had a significant increase in leukocyte count directly after protamine administration (p < 0.0001) and elastase release during cardiopulmonary bypass that was significantly higher in patients with multiple system organ failure than in those without (p < 0.05). Consumption of prekallikrein as an indicator of activation of the Hageman system was not detectable during cardiopulmonary bypass in any child. After cardiopulmonary bypass, in patients without multiple system organ failure, C3d/C3 decreased and reached preoperative values within the first postoperative week, whereas, in patients with multiple system organ failure, C3d/C3 increased further, reaching a maximal value on the third postoperative day. In comparison with patients without multiple system organ failure, patients with multiple system organ failure showed a severe decrease of C4 (with minimal values on the third postoperative day), suggesting consumption by activation of the classic pathway of the complement system or a hepatic synthesis deficiency. Prekallikrein values were also significantly lower in patients with multiple system organ failure than in the others, with a maximal difference on the third postoperative day (p < 0.005). C-reactive protein was significantly lower in patients with multiple system organ failure than in the others for the first 2 postoperative days (p < 0.05), probably because of severe hepatic failure in patients with multiple system organ failure. This study demonstrates that, in children, cardiopulmonary bypass induces complement activation principally via the alternative pathway. It suggests a relationship between complement activation and multiple system organ failure observed in the postoperative period. Furthermore, it points out the role of multiple system organ failure itself on the C3 conversion and on the synthesis of the markers of the inflammatory response in children after heart operations.