ObjectivesTo investigate heterogeneity in the cost-effectiveness of high-flow nasal cannula (HFNC) therapy compared with continuous positive airway pressure (CPAP) for acutely ill children requiring noninvasive respiratory support. MethodsUsing data from the First-line Support for Assistance in Breathing in Children trial, we explore heterogeneity at the patient and subgroup levels using 2 causal forest approaches and a seemingly unrelated regression approach for comparison. First-line Support for Assistance in Breathing in Children is a noninferiority randomized controlled trial (ISRCTN60048867) involving 24 UK pediatric intensive care units. The Step-up trial focuses on acutely ill children aged 0 to 15 years, requiring noninvasive respiratory support. A total of 600 children were randomly assigned to HFNC and CPAP groups in a 1:1 allocation ratio, with 94 patients excluded because of data unavailability. ResultsThe primary outcome is the incremental net monetary benefit (INB) of HFNC compared with CPAP, using a willingness-to-pay threshold of £20 000 per quality-adjusted life year gain. INB is derived from total costs and quality-adjusted life years at 6 months. Subgroup analysis showed that some subgroups, such as male children, those aged less than 12 months, and those without severe respiratory distress at randomization, had more favorable INB results. Patient-level analysis revealed heterogeneity in INB estimates, particularly driven by the cost component, with greater uncertainty for those with higher INBs. ConclusionsThe estimated overall INB of HFNC is significantly larger for specific patient subgroups, suggesting that the cost-effectiveness of HFNC can be heterogeneous, which highlights the importance of considering patient characteristics in evaluating the cost-effectiveness of HFNC.