<b><i>Introduction</i></b>: Asthmatics can experience recurrent exacerbations (AEs), irrespectively of asthma severity. Airway inflammatory monitoring could be fundamental to optimize the asthma management. The present study evaluated whether exhaled NO concentrations in proximal and distal respiratory compartments are different in AE-prone patients in combination with T2 blood biomarkers and resting oxygen saturation (SpO₂). <b><i>Methods</i></b>: In this observational cross-sectional study, 91 mild-to-severe asthmatics were enrolled. Clinical characteristics, blood and lung function parameters including SpO₂, and F_ENO were evaluated. On 50 randomly selected patients, C_ANO and J_awNO were also analyzed. Then, patients were stratified in frequent exacerbators (FEs) or non-frequent exacerbators (nFEs), according to AE frequency in the previous year (phase I). Chart data were re-evaluated through a 12-month follow-up period post exhaled NO measurement to detect occurrence of novel AE (phase II). <b><i>Results</i></b>: FE asthmatics had poorer asthma control and required higher therapeutic intensity (<i>p</i> &#x3c; 0.05). F_ENO, C_ANO, and J_awNO were similar between FE and nFE. FE exhibited higher total serum IgE levels and residual volume values but reduced SpO₂ than nFE (<i>p</i> &#x3c; 0.05); SpO₂&#x3c;96.5% characterized the FE patient (odds ratio = 2.94). In phase II, C_ANO was higher in the group with novel AE at 1-month post-NO measurement (<i>p</i> &#x3c; 0.05), but not afterward. A higher prevalence of C_ANO &#x3e;6 ppb was detected in asthmatics who developed AE within 1 month, suggesting its potential clinical use as biomarker in predicting near-future AE (RR = 11.20). <b><i>Conclusion</i></b>: AE-susceptible asthmatics are characterized by air trapping and distal airway inflammation in conjunction with lower oxygen saturation. C_ANO and SpO₂ could exert specific roles, respectively, in predicting AE and monitoring FE asthmatics.

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