Fluid management is challenging in infants after cardiopulmonary bypass. Pulse pressure variation (PPV) derived from pressure recording analytical method (PRAM) is based on lung-heart interaction during mechanical ventilation. A prospective observational study conducted in operating room tested PPV to predict fluid responsiveness in ventricular septal defect infants. Infants in open chest conditions with median sternotomy (n = 26) or minimally invasive right thoracotomy (n = 29) undergoing ventricular septal defect repair were enrolled. After cardiopulmonary bypass and modified ultrafiltration, all patients received fluid challenge. PPV was recorded using PRAM along with heart rate, diastolic blood pressure, stroke volume index (SVI), and cardiac index (CI) before and after volume replacement. Patients were considered as responders to fluid loading when CI increased C15%. In infants with median sternotomy, 12 were responders and 14 non-responders. PPV in responders was higher than that in non-responders (24.7 +/- 6.4 vs. 16.6 +/- 5.0%, P< 0.01). Area under the curve was 0.85 (95% confidence interval, 0.69-1, P = 0.001) and cutoff value 19% with a sensitivity of 92% and a specificity of 71%. In infants with minimally invasive right thoracotomy, 16 were responders and 13 non-responders. PPV in responders was higher than that in non-responders (25.0 +/- 6.8 vs. 18.2 +/- 5.3, P< 0.01). Area under the curve was 0.83 (95 confidence interval, 0.66-0.98, P = 0.001) and cutoff value 18% with a sensitivity of 94% and a specificity of 69%. PPV sensitively predicts fluid responsiveness in ventricular septal defect infants after surgical repair in open chest conditions both with median sternotomy and minimally invasive right thoracotomy.