ObjectivesThe 22‐question SinoNasal Outcome Test (SNOT‐22) assesses chronic rhinosinusitis (CRS) severity. We aimed to identify predictors of SNOT‐22 score improvement following highly effective modulator therapy (HEMT) initiation and to corroborate the SNOT‐22 minimal clinically important difference (MCID) in adults with cystic fibrosis (CF).MethodsProspective observational data was pooled from four studies across 10 US centers investigating people with CF (PwCF) and CRS. Three studies evaluated HEMT's impact on CRS. For participants enrolled prior to HEMT initiation, SNOT‐22 scores were obtained at baseline and after 3–6 months of HEMT. Multivariate regression identified predictors of improvement. Cronbach's alpha and four distribution‐based methods were used to assess internal consistency and calculate the MCID of the SNOT‐22.ResultsA total of 184 PwCF participated with mean baseline SNOT‐22 scores ranging from 18.1 to 56.7. Cronbach's alpha was ≥0.90 across sites. Participants at sites with pre‐ and post‐HEMT data reported improvement in SNOT‐22 scores after initiating HEMT (all p < 0.05). Worse baseline SNOT‐22 score (odds ratio (OR): 1.05, p < 0.001, 95% CI: 1.02–1.08), F508del homozygosity (OR: 4.30, p = 0.040, 95% CI: 1.14–18.99), and absence of prior modulator therapy (OR: 4.99, p = 0.017, 95% CI: 1.39–20.11) were associated with greater SNOT‐22 improvement. The mean MCID calculated via distribution‐based methods was 8.5.ConclusionWorse baseline sinonasal symptoms, F508del homozygosity, and absence of prior modulator therapy predicted greater improvement after HEMT initiation. The mean MCID for SNOT‐22 in PwCF is 8.5 points, similar to non‐CF individuals with CRS, and provides a threshold specifically for PwCF. The SNOT‐22 has strong internal consistency in PwCF.Level of Evidence3 Laryngoscope, 2024