Approximately 50% of adults on long-term asthma medication are non-adherent. Current methods to detect non-adherence have had limited effect. Fractional exhaled nitric oxide suppression testing (FeNOSuppT) has demonstrated clinical effectiveness as an adherence screening tool to detect poor adherence to inhaled corticosteroids in difficult-to-control asthma prior to initiation of expensive biologic therapy. Estimate the cost-effectiveness and budget impact of FeNOSuppT as a screen prior to the initiation of biologic therapy among US adults with difficult-to-control asthma and high FeNO (≥45ppb). A decision tree simulated the progression of a cohort of patients over a one year time horizon into one of three states [discharged from (1) or remain in (2) specialist care; or progress to biologics (3)]. Two strategies, with and without FeNOSuppT, were examined and the incremental net monetary benefit (INMB) estimated using a discount rate of 3% and a willingness to pay (WTP) threshold of $100,000 per quality-adjusted life year (QALY). Sensitivity analysis and a budget impact analysis were also undertaken. In the baseline scenario, FeNOSuppT prior to the initiation of biologic therapy was associated with lower costs ($4,435/patient) and fewer QALYs (0.0023QALY/patient) compared to no-FeNOSuppT over one year and was considered cost-effective (INMB=$4,207). FeNOSuppT was consistently found to be cost-effective across a range of scenarios and in deterministic and probabilistic sensitivity analyses. Assuming differential levels of FeNOSuppT uptake (20%-100%), this was associated with budget savings ranging from USD $5m-$27m. FeNOSuppT is likely to be cost-effective as a protocol-driven, objective, biomarker-based tool for identifying non-adherence in difficult-to-control asthma. This cost-effectiveness is driven by cost-savings from patients not progressing to expensive biologic therapy.