Serum levels of soluble fms-like tyrosine kinase 1 (sFlt-1), an antiangiogenic factor, and its binding protein, placental growth factor (PlGF), are altered in women with preeclampsia. Recently, the sFlt-1/PlGF ratio has been shown to predict acute coronary syndrome in adults. However, few reports have described the use of the sFlt-1/PlGF ratio for evaluating an abnormal hemodynamic load in children with congenital heart disease (CHD). The sFlt-1/PlGF ratio was determined in 20 children with atrial septal defects (ASD), 26 children with ventricular septal defects (VSD), 57 children with tetralogy of Fallot (ToF), 35 children who were Fontan candidates (Fontan), and 14 controls. The preoperative sFlt-1/PlGF ratios in the ASD, VSD, and Fontan were significantly higher than those in the controls and were significantly decreased after surgical repair in the ASD and VSD. In the ToF, the sFlt-1/PlGF ratio was highest after first-stage repair and second-highest after final-stage palliation compared with the preoperative levels. The sFlt-1/PlGF ratio was highest after first-stage repair and much lower after final-stage palliation in the Fontan. Furthermore, these ratios correlated with the degree of the ventricular volume overload and hypoxia. Our study clearly demonstrated that the sFlt-1/PlGF ratio increases with volume overload and persistent hypoxia after surgery with CHD. These findings may prove useful in the management of CHD in children.