To investigate the relationship between cigarette smoking and the level of circulating natural killer (NK) cells, we studied 282 subjects from a population-based, stratified random sample of healthy persons. NK cells were enumerated by flow cytometry using the monoclonal antibody anti-Leu 11A. Cigarette smokers had a significantly lower proportion of NK cells than did subjects who had never smoked (5.5 +/- 0.3% versus 7.4 +/- 0.4% of lymphoid cells; p = 0.0002). NK cells were also decreased among ex-smokers (5.6 +/- 0.4%; p = 0.002), including subjects who had not smoked for more than 20 yr. The white blood cell and lymphocyte counts were increased in smokers compared with those in never smokers (p less than 0.0001). In contrast to NK cells, the smoking-related changes in leukocyte count were not present in ex-smokers, even those who had stopped smoking within the past year. Multivariate analysis confirmed that both current and past smokers had significant decreases in both the number and proportion of NK cells after controlling for age, sex, and lymphocyte count. These data indicate that cigarette smoking is associated with a decrease in the number and proportion of circulating NK cells, and that this effect is present many years after smoking cessation. This quantitative NK cell deficit may contribute to the elevated risk of malignancy in this population.