Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels increase after cardiopulmonary bypass (CPB) in pediatric patients. However, the exact reason for the postoperative increase remains unclear. This study elucidated the perioperative changes in plasma natriuretic peptide levels in children undergoing surgical isolated atrial septal defect (ASD) closure. Between 2010 and 2012, 24 pediatric patients (median 7.1, range 2.7–15.7 years) underwent surgery for simple ASD using CPB under ventricular fibrillation (Group A, 16 patients) or under cardiac arrest (Group B, 8 patients). Natriuretic peptide levels were measured before surgery, on postoperative day 0, 1, 3, and at the first outpatient visit. The pulmonary to systemic blood flow ratio (Qp/Qs) was estimated by echocardiography using an index of right ventricle end-diastolic area. Preoperative natriuretic peptide levels positively correlated with the Qp/Qs. Plasma ANP levels peaked on postoperative day 0, and its values were higher in Group A than in Group B patients (p < 0.001). Plasma BNP levels increased significantly in both Groups on postoperative day 1, and its values were significantly greater in Group A than in Group B patients (p = 0.007). There was a weak negative correlation between the amount of postoperative increase in natriuretic peptide levels and the Qp/Qs. There was no appreciable difference in the acute postoperative clinical course and echocardiographic parameter on postoperative day 3 between Group A and B patients. In conclusion, acute postoperative natriuretic peptide levels after isolated ASD closure were multifactorial, and they might be unreliable for predicting clinical outcomes.