Rationale: Club (Clara) cell protein 16 (CC-16) is a protein that is synthesized predominantly in the lungs and is detectable in serum. Its expression decreases with lung injury and smoking and is thus a marker of bronchial cell dysfunction. Objectives: To evaluate the possibility of using serum CC-16 as a biomarker for disease progression in chronic obstructive pulmonary disease. Methods: We measured serum CC-16 levels from 4,724 subjects with mild-to-moderate airflow limitation in the Lung Health Study. Using a linear regression model, we determined the relationship of serum CC-16 concentrations to decline in lung function over 9 years. Additionally, to determine whether CC-16 plays a major role in the pathogenesis of mild COPD, we exposed CC-16 deficient mice (-/-) to 6 months of cigarette smoke. Measurements and Main Results: Reduced serum concentrations of CC-16 were associated with accelerated decline in forced expiratory volume in 1 second (FEV1) over 9 years (p<0.0001), and this association persisted after adjustments for age, gender, race, smoking status, airway reactivity, body mass index and baseline FEV1 (p=0.0006). However, CC-16 -/- mice did not demonstrate an enhanced risk of emphysema or small airway remodeling in response to cigarette smoke. Conclusions: Serum CC-16 is associated with disease progression and may assist in the identification of "rapid progressors". However, the absence of CC-16 does not appear to modify the risk of cigarette-related COPD in mice.