This study compared airway responsiveness in vitro, as measured in isolated bronchi, with responsiveness in vivo in patients with COPD and smokers with normal lung function. In 9 patients with COPD (mean (range) FEV, 55 (30-78) %predicted) and 8 smokers with normal lung function (FEV1 101 (89-117) %predicted), who underwent surgery for lung cancer, responses to inhaled histamine and salbutamol were assessed before surgery. Bronchial specimens of 1-4 mm internal diameter were studied in the organ bath and histamine concentration-response curves assessed. All patients with COPD and none of the control individuals were hyperresponsive to inhaled histamine. Five patients with COPD and no control patient showed a bronchodilator response to salbutamol. Opposite to these findings, bronchial rings in the organ bath demonstrated a rightward shift of histamine concentration-response curves in COPD compared to controls, (p < 0.005). Accordingly, pED50 but not Emax differed statistically (p = 0.0016) between groups, mean+/-SEM values of pED50 in COPD (controls) being 4.67+/-0.08 (5.29+/-0.15) and of Emax 672+/-86 (772+/-120) mg. Patients with COPD showing hyperresponsiveness to inhaled histamine demonstrated lower responsiveness of their isolated bronchi compared to smokers with normal lung function. This suggests that in vivo hyperresponsiveness is based on other mechanisms than alterations in smooth muscle physiology.