Airway hyperresponsiveness (AHR) is one of the characteristics of asthma and a risk factor for persistent airflow limitation. Poor response to bronchodilator may be a cause of persistent airflow limitation. Multiple factors may determine bronchodilator responsiveness, including airway reactivity to nonspecific bronchoconstrictive agents. If patients with AHR have poor bronchodilator responsiveness, then it could be a potential mechanism for asthma and persistent airflow limitation in these patients. The objective of this study is to assess the relationship between airway reactivity to methacholine and responsiveness to beta-agonist and beta-agonist/anticholinergic combination in a large subject population. A retrospective data analysis was undertaken of 764 consecutive subjects with > or = 20% reduction in forced expiratory volume during the first second of exhalation from total lung capacity (FEV1) after < or = 189 cumulative units of methacholine. The first 382 subjects received 3 inhalations of metaproterenol and the second 382 subjects received 3 inhalations of albuterol and ipratropium combination after > or = 20% reduction in FEV1. Bronchodilator responsiveness was measured as the percent increase in FEV1 after the treatment. Airway reactivity was assessed as the log10 of methacholine dose response slope. In a simple linear regression model, airway reactivity was significantly related to bronchodilator responsiveness. The coefficient of determination (r2) was 0.15 for the whole groups; 0.14 for metaproterenol group and 0.18 for albuterol/ipratropium combination group (all p<0.0001). The regression coefficient (beta) was 14.0 for the whole group; 14.8 and 13.2, respectively, for the two bronchodilator groups. Airway reactivity to methacholine is a determinant of airway responsiveness to both beta-agonist and beta-agonist/anticholinergic combination. Subjects with higher airway reactivity have higher bronchodilator responsiveness.