Circulating levels of CC-16 have been linked to Clara cell toxicity and so this protein has been suggested as a marker of COPD. Serum CC-16 was measured in 2083 individuals aged 40-75 years with COPD and a smoking history of ≥10 pack years, 332 controls with a smoking history ≥10 pack years and normal lung function and 237 non-smoking controls. Serum CC-16 had a coefficient of repeatability of 2.90 over 3 months in a pilot study of 267 individuals. The median level of serum CC-16 was significantly reduced in a replication group of 1888 current and former smokers with COPD when compared to 296 current and former smokers without airflow obstruction (4.9 and 5.6 ng/mL; p<0.001) and 201 non-smokers (6.4 ng/mL; p<0.001). Serum levels of CC-16 were lower in current rather than former smokers with GOLD stage II and III COPD but were not different in individuals with stage IV disease. Former, but not current smokers, with COPD had lower serum CC-16 with increasing severity of COPD (GOLD II vs GOLD IV COPD; 5.5 and 5.0 ng/mL p=0.006; r=0.11 with FEV1, p<0.001) and had significantly higher levels if they also had reversible airflow obstruction (p=0.034). Serum CC-16 was affected by gender and age (r=0.35; p<0.001) in subjects with COPD but not by BMI or the presence of either chronic bronchitis or emphysema. These data show that serum CC-16 is reduced in individuals with COPD and that there is a weak correlation with disease severity in former smokers.