Background Despite the increasing use of non-invasive respiratory support in paediatric intensive care units, there are no large randomised controlled trials comparing two commonly used non-invasive respiratory support modes, continuous positive airway pressure and high-flow nasal cannula therapy. Objective To evaluate the non-inferiority of high-flow nasal cannula, compared with continuous positive airway pressure, when used as the first-line mode of non-invasive respiratory support in acutely ill children and following extubation, on time to liberation from respiratory support, defined as the start of a 48-hour period during which the child was free of respiratory support (non-invasive and invasive). Design A master protocol comprising two pragmatic, multicentre, parallel-group, non-inferiority randomised controlled trials (step-up and step-down) with shared infrastructure, including internal pilot and integrated health economic evaluation. Setting Twenty-five National Health Service paediatric critical care units (paediatric intensive care units and/or high-dependency units) across England, Wales and Scotland. Participants Critically ill children assessed by the treating clinician to require non-invasive respiratory support for (1) acute illness (step-up randomised controlled trial) or (2) within 72 hours of extubation (step-down randomised controlled trial). Interventions High-flow nasal cannula delivered at a flow rate based on patient weight (Intervention) compared to continuous positive airway pressure of 7–8 cm H2O pressure (Control). Main outcome measures The primary clinical outcome was time to liberation from respiratory support. The primary cost-effectiveness outcome was 180-day incremental net monetary benefit. Secondary outcomes included mortality at paediatric intensive care unit/high-dependency unit discharge, day 60 and day 180; (re)intubation rate at 48 hours; duration of paediatric intensive care unit/high-dependency unit and hospital stay; patient comfort; sedation use; parental stress; and health-related quality of life at 180 days. Results In the step-up randomised controlled trial, out of 600 children randomised, 573 were included in the primary analysis (median age 9 months). Median time to liberation was 52.9 hours for high-flow nasal cannula (95% confidence interval 46.0 to 60.9 hours) and 47.9 hours (95% confidence interval 40.5 to 55.7 hours) for continuous positive airway pressure (adjusted hazard ratio 1.03, one-sided 97.5% confidence interval 0.86 to ∞). The high-flow nasal cannula group had lower use of sedation (27.7% vs. 37%) and mean duration of acute hospital stay (13.8 days vs. 19.5 days). In the step-down randomised controlled trial, of the 600 children randomised, 553 were included in the primary analysis (median age 3 months). Median time to liberation for high-flow nasal cannula was 50.5 hours (95% confidence interval, 43.0 to 67.9) versus 42.9 hours (95% confidence interval 30.5 to 48.2) for continuous positive airway pressure (adjusted hazard ratio 0.83, one-sided 97.5% confidence interval 0.70 to ∞). Mortality at day 180 was significantly higher for high-flow nasal cannula [5.6% vs. 2.4% for continuous positive airway pressure, adjusted odds ratio, 3.07 (95% confidence interval, 1.1 to 8.8)]. Limitations The interventions were unblinded. A heterogeneous cohort of children with a range of diagnoses and severity of illness were included. Conclusions Among acutely ill children requiring non-invasive respiratory support, high-flow nasal cannula met the criterion for non-inferiority compared with continuous positive airway pressure for time to liberation from respiratory support whereas in critically ill children requiring non-invasive respiratory support following extubation, the non-inferiority of high-flow nasal cannula could not be demonstrated. Future work (1) Identify risk factors for treatment failure. (2) Compare protocolised approaches to post-extubation non-invasive respiratory support, with standard care. (3) Explore alternative approaches for evaluating heterogeneity of treatment effect. (4) Explore reasons for increased mortality in high-flow nasal cannula group within step-down randomised controlled trial. Study registration Current Controlled Trials ISRCTN60048867. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/94/28) and is published in full in Health Technology Assessment; Vol. 29, No. 9. See the NIHR Funding and Awards website for further award information.