Introduction: Fractional exhaled nitric oxide (FENO) may be a useful objective measurement to guide asthma treatment. What remains uncertain is what change in FENO is clinically significant. Methods: An individual patient data analysis was performed using data from seven randomized clinical trials which used FENO to guide asthma treatment. The absolute and percentage intra-subject change in FENO measurements over “stable” and also “unstable” 3-month periods were described. Results: Data were available in 1112 randomized controlled trial participants and ≥1 stable period was present for 665 individuals. The interquartile range (IQR) and limits of agreement (LoA) for change in absolute FENO among individuals whose initial FENO was <50 parts per billion (ppb) were −7 to +9 ppb and −43 to +50 ppb, and for those with initial FENO ≥50 ppb IQR was −29 to +17 ppb and LoA was −80 to +76 ppb. For percentage change in FENO, the IQR and LoA for individuals whose initial FENO was <50 ppb were −33% to +51% and −157% to +215%, and for those with initial FENO ≥50 ppb were −33% to +35% and −159% to +192%. The variation in FENO values for a stable period was similar irrespective of whether it was followed by a stable or unstable period. Conclusions: Over a 3-month period where FENO is initially <50 ppb, a rise of <10 ppb or of <50% (based on IQR) is unlikely to be related to asthma. When FENO is initially ≥50 ppb an percentage change of <50% (based on IQR) is unlikely to be asthma-related.