Objectives: Cardiopulmonary bypass generates a systemic inflammatory response. This inflammatory response is reduced if patients are ventilated during bypass, as evidenced by lower levels of postoperative circulating inflammatory mediators. However, this does not appear to make much clinical difference in adults, at least not consistently, but, to our knowledge, has never been assessed in paediatric cardiac surgery, which is the objective of this study., Methods: This is a prospective clinical study of 12 consecutive neonates operated for the correction of either transposition of the great arteries ± ventricular septal defect or aortic arch hypoplasia ± ventricular septal defect, who were ventilated during cardiopulmonary bypass. These were compared to 11 neonates with the same malformations, who had undergone the same operations but without being ventilated during bypass (historical control group)., Results: One patient from the control group died on the 15th postoperative day due to sepsis and multi-organ failure. Bypass times and cross-clamp times were similar in the 2 groups. Ventilation on bypass was associated with significantly lower postoperative serum concentrations of C-reactive protein, shorter mechanical ventilation and lower vasoactive-inotropic score. Duration of stay on intensive care unit (ICU) showed a tendency to be shorter in patients who were ventilated on bypass, but this did not reach statistical significance. There were no differences between the 2 groups with respect to postoperative mixed venous oxygen saturations and serum concentrations of lactate and troponin I., Conclusions: Mechanical ventilation during cardiopulmonary bypass in neonates improves postoperative outcome., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)