Patients with congenital heart disease (CHD) that have surgical repair with cardiopulmonary bypass (CPB) reflect a unique population with multiple pulmonary and systemic factors that may contribute to increased alveolar dead space and low cardiac output syndrome. This study aimed to assess and compare changes in the alveolar dead space fraction (AVDSf) in the immediate postoperative period with outcomes in children with CHD who underwent repair on CPB. A single-center retrospective review study of critically ill children with CHD, younger than 18 years of age admitted to the Pediatric Intensive Care Unit (PICU) after undergoing surgical repair on CPB and received invasive mechanical ventilation for at least 24 h. One hundred and two patients were included in the study. Over the first 24 h, mean AVDSf was significantly higher in patients who had longer hospital length of stay (LOS) (> 21 days) p = 0.02, and longer duration of invasive mechanical ventilation (DMV) (> 170 h) p = 0.01. Cross-sectional analyses at 23–24 h revealed that AVDSf > 0.25 predicts mortality and DMV ( p = 0.03 and P = 0.02 respectively); however, it did not predict prolonged hospital LOS. For every 0.1 increase in the AVDSf, the odds of mortality, DMV, and hospital LOS increased by 4.9 [95% CI = 1.45–16.60, p = 0.002], 2.06 [95% CI = 1.14–3.71, p = 0.01], and 1.43[95% CI = 0.84–2.45, p = 0.184], respectively. The area under the ROC curve at 23–24 h for AVDSf was 0.868 to predict mortality as an outcome. AVDSf > 0.25 at 23–24 h postoperatively was an independent predictor of mortality with sensitivity and specificity of 83% and 80%, respectively and was superior to other commonly used surrogates of cardiac output. In the immediate postoperative period of pediatric patients with CHD, high AVDSf is associated with longer hospital length of stay and duration of invasive mechanical ventilation. Increased AVDSf values at 23–24 h postoperatively is associated with mortality in patients with CHD exposed to CPB. Supplementary Information The online version contains supplementary material available at 10.1007/s00246-021-02674-2.