Clara cell protein (CC16) is a 16-kDa protein secreted by Clara cells and other nonciliated cells of both the bronchiolar and bronchial epithelium. CC16 is present in high concentrations in the respiratory tract secretions but occurs also in other fluids such as serum. In this study, CC16 has been measured in the sera from 65 female and 69 male current smokers and in a sex- and age-matched control group of 135 neversmokers. Lifetime smoking averaged (geometric mean) 12.7 (range, 0.6 to 61.3) and 17.9 (range, 0.8 to 126) pack-years in female and male smokers, respectively. A significant reduction of Clara cell protein was found in the sera of smokers of both sexes. In neversmokers serum CC16 was independent of sex but significantly increased with age. In current smokers serum CC16 was also negatively correlated with both the current and lifetime cigarette consumption and with the 24-h urinary excretion of thiocyanate. After adjustment for age, a linear dose-response relation was apparent between smoking history and serum CC16, the latter decreasing on average by about 15% for each 10 pack-year smoking history. The present study supports the concept that CC16 in serum is a marker of bronchial dysfunction caused by tobacco smoke. As CC16 appears to be a natural immunosuppressor of the respiratory tract, its decreased production might explain some inflammatory changes associated with smoking.