Inhaled acetaldehyde may induce bronchoconstriction in asthmatic subjects and provides a new method to investigate airway responsiveness. The objective of the study was to determine whether acetaldehyde was a more specific stimulus than methacholine in differentiating asthma from chronic bronchitis with or without airflow limitation. Bronchial provocation challenges with methacholine and acetaldehyde were performed in 62 asthmatics and in 59 smokers with chronic bronchitis (32 with chronic bronchitis alone and 27 with chronic bronchitis and coexisting chronic obstructive pulmonary disease (COPD)). The response to both bronchoconstrictor agents was measured by the provocative concentration required to produce a 20% fall in forced expiratory volume in one second (FEV1; PC20). The two types of challenge yielded a similarly high level of sensitivity (100% for methacholine and 92% for acetaldehyde) in revealing airway hyperresponsiveness in asthma. However, bronchoprovocation with acetaldehyde yielded considerably greater specificity (95%) than bronchoprovocation with methacholine (24%) in separating asthma from chronic bronchitis. In subjects with asthma, methacholine and acetaldehyde responsiveness were weakly but significantly correlated (r=0.42, p=0.001) but no correlation was found between airway responsiveness to acetaldehyde and baseline FEV1 (r=0.13, p=0.33). These findings suggest that the demonstration of bronchoconstriction in response to acetaldehyde may be a more specific test than methacholine in the differentiation of asthma from chronic bronchitis. Furthermore, methacholine and acetaldehyde hyperresponsiveness are not reflecting the same pathophysiological process in the airways.