To study the question of bronchial responsiveness as a risk factor for chronic air-flow limitation, we measured the response to inhaled isoproterenol in 795 subjects drawn from 2 cohorts that have been followed over a 9 to 11-yr period. A matched analysis was also performed comparing 44 responsive subjects from these cohorts with 132 nonresponsive control subjects. In both cohorts, level of response to isoproterenol was associated with rate of decline of FEV1 only among "responsive" subjects. These results were confirmed by the matched analysis in which rate of decline of FEV1 among responsive subjects was significantly greater than that observed in their matched controls. These differences were present among smokers as well as nonsmokers and among subjects with and without doctor-diagnosed chronic bronchitis and asthma. We conclude that bronchial hyperresponsiveness is associated with an accelerated decline of FEV1 in nonsmokers and ex-smokers as well as in smokers, and that the relationship exists before clinical disease is manifest. Further work needs to be done to determine whether the association is causal or merely indirect.