The effect of cardiopulmonary bypass (CPB) on various blood parameters in children undergoing major cardiovascular surgery was investigated in a prospective clinical study. Blood samples of children with CPB (CPB group, n = 18) or without CPB (control, n = 12) were collected before, during, and after surgery. The concentration of routine laboratory parameters, components of the complement system (C3, C4, C5, C1 inhibitor, total hemolytic complement, C3d, and C5a), circulating interleukins (IL-6 and IL-8) and soluble adhesion molecules (sICAM-1 and sE-selectin) were determined. In both groups of patients the serum concentrations of C3, C4, C5, and C1 inhibitor were significantly affected by the treatments (p < 0.001), decreased immediately after onset of anesthesia, were minimal during surgery, and increased thereafter. No significant differences in the kinetics of these parameters were detectable between CPB and control group. In the CPB group the activation of the alternative pathway (increased C3d) was found to be a specific response (p = 0.005), but also in the control group C3d and C5a concentration increased significantly (p < 0.022), indicating complement activation. None of the effects that would be expected after activation of the complement system were specific for the CPB group. In both groups the serum levels of IL-6 increased dramatically during and/or after surgery (p = 0.001), and IL-8 was detectable after surgery in 10/12 control patients. The concentration of sICAM-1 and sE-selectin decreased during surgery (p < 0.04) and later did not increase above baseline. Our data suggest that increased serum levels of inflammation mediators and increased consumption of complement and adhesion molecules occur during cardiovascular surgery. Although complement activation and ICAM-1 consumption are more pronounced in the CPB patients, none of these changes occurs exclusively in the CPB group. We conclude, therefore, that these changes are the combined effect of anesthesia, surgical trauma, and endothelial lesions. Additional, undefined CPB-induced reactions may also contribute the postoperative morbidity.