OBJECTIVE Cardiopulmonary bypass induces an ischaemia-reperfusion injury and systemic inflammatory response, which contributes to low cardiac output syndrome following cardiac surgery. Exogenous nitric oxide during cardiopulmonary bypass has shown potential to ameliorate such injury. We undertook a large randomised controlled trial to investigate the clinical effects of administering nitric oxide to the cardiopulmonary bypass circuit in children. METHODS After written informed consent, children were randomised to receive 20 ppm nitric oxide to the gas inflow of the cardiopulmonary bypass oxygenator, or standard conduct of bypass. RESULTS 101 children received nitric oxide and developed low cardiac output syndrome less frequently (15 vs. 31 %, p = 0.007) than the 97 children who did not receive nitric oxide. This effect was most marked in children aged less than 6 weeks of age (20 vs. 52 %, p = 0.012) and in those aged 6 weeks to 2 years (6 vs. 24 %, p = 0.026), who also had significantly reduced ICU length of stay (43 vs. 84 h, p = 0.031). Low cardiac output syndrome was less frequent following more complex surgeries if nitric oxide was administered (17 vs. 48 %, p = 0.018). ECMO was used less often in the nitric oxide group (1 vs. 8 %, p = 0.014). CONCLUSIONS Delivery of nitric oxide to the oxygenator gas flow during paediatric cardiopulmonary bypass reduced the incidence of low cardiac output syndrome by varying degrees, according to age group and surgery complexity. BACKGROUND ACTRN12615001376538.