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Club cell secretory protein (CC-16) is a sensitive biomarker of airways epithelium integrity. It has gained interest as a biological marker in chronic lung diseases because of its presumed relationship to inflammation. Little is known about the association between CC-16 serum level and asthma, lung function and airway responsiveness (AR).Serum CC-16 level was determined by latex immunoassay in 1298 participants from the French Epidemiological case-control and family-based study on Genetics and Environment of Asthma (EGEA) (mean age 43 years; 49% men, 38% with asthma). Pre-bronchodilator lung function (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC) and degree of AR, expressed as a function of the dose–response slope to methacholine test were measured. Standardized residuals CC-16 z-scores were obtained by regressing CC-16 level on the glomerular filtration rate. CC-16 z-scores were correlated with asthma, lung function and AR in participants with and without asthma.CC-16 geometric mean level was 12.4 μg/L (range: 2.2–70.6 μg/L). In participants without asthma, lower CC-16 z-scores was associated with impaired FEV1/FVC% (β = 0.50 (95% CI: 0.06, 0.95) and with higher degree of AR (β = 0.24 (95% CI: 0.09, 0.39)). CC-16 was not associated with impaired lung function or AR in participants with asthma.Lower CC-16 serum level was associated with impaired lung function and AR, suggesting that serum CC-16 level may reflect early damages to the lung epithelium in adults without asthma.