We compared plasma levels of the neutrophil elastase-derived fibrinopeptide A-alpha-1-21 in healthy cigarette smokers with those in nonsmokers. The mean A-alpha-1-21 concentration was fivefold higher (95% confidence interval [CI], 3.0 to 9.6) in ten cigarette smokers than in 20 healthy nonsmokers (2.0 nmol/L compared with 0.4 nmol/L; p less than 0.0001). To evaluate the acute effect of smoking on enzyme activity, a second group of ten smokers was studied. After refraining from smoking for 12 hours, each person smoked three cigarettes. The mean A-alpha-1-21 level in the second group of smokers was not different from that in the first group of smokers (1.8 nmol/L compared with 2.0 nmol/L) but was fivefold higher (95% CI, 2.6 to 8.7) than that in the nonsmokers (1.8 nmol/L compared with 0.4 nmol/L; p less than 0.0001). After smoking three cigarettes, subjects had a twofold elevation (95% CI, 1.6 to 3.5) in the mean A-alpha-1-21 concentration (from 1.8 nmol/L to 4.1 nmol/L; p = 0.002). Our data show that cigarette smoking perturbs the in-vivo elastase-antielastase balance and thus may produce lung disease through this mechanism.