BackgroundQuantitative mucus cytokine analysis to examine the sinonasal microenvironment may bridge the gap between patient‐reported outcome measures (PROMs) and empirical measures of inflammation in patients with chronic rhinosinusitis (CRS).ObjectiveInvestigate the correlation between mucus cytokine levels and Sino‐Nasal Outcome Test (SNOT‐22) scores, including individual subdomains.MethodsPatients with CRS were prospectively recruited between 2016 and 2021 into a multi‐institutional observational study. Mucus was collected from the olfactory cleft and evaluated for mucus cytokine biomarkers. Spearman correlations (ρ) between cytokine levels and SNOT‐22 scores, including individual subdomains, Lund–Mackay (LM) CT and Lund–Kennedy (LK) endoscopy scores were assessed. Subgroup analysis based on nasal polyp status (CRSsNP—without nasal polyps; CRSwNP—with nasal polyps) was also performed. Linear regression was employed to identify multivariate associations between cytokine expression levels, clinical covariates, and SNOT‐22 total and domain scores.ResultsA total of 127 patients were included in the study (CRSsNP = 53, CRSwNP = 74). IL‐9 (ρ = 0.196, p < 0.05) was the only biomarker that correlated with the SNOT‐22 total score. CRSwNP patients had a higher absolute expression level of Type 2 biomarkers (IgE, IL‐5, and IL‐13), compared to CRSsNP patients. IgE, IL‐5, IL‐9, and IL‐13 significantly correlated with the SNOT‐22 rhinologic subdomain scores (p < 0.001), LM scores, and patient reported sense of smell (Question 21). Notably, subgroup analysis showed that CRSsNP patients also demonstrated significant correlations between Type 2 markers (IL‐4, IL‐5, IL‐9, and IL‐13) and SNOT‐22 rhinologic subdomain scores.ConclusionType 2 mucus cytokine levels, especially IL‐9, correlate with SNOT‐22, and the rhinologic SNOT‐22 subdomain scores for both CRSsNP and CRSwNP patients.