The present study was designed to evaluate the bronchodilating role of zafirlukast, a CysLT1receptor antagonist, at the standard dosage currently recommended in the marketing of this agent in smokers with COPD. The study was performed using a double-blind, cross-over, randomized design and was conducted on 2 non-consecutive days. Sixteen outpatients suffering from stable COPD received 40 mg oral zafirlukast, or placebo. Lung function was controlled before drug administration and 30, 60, 120, 180, 240 min thereafter. At the end of the 4-h period, each patient received 400 μg inhaled salbutamol and spirometric testing was performed 30 min later. Zafirlukast, but not placebo, produced a significant (P<0.05) bronchodilation between 30 min and 4 h following administration, with a maximum mean increase in FEV1of 0.134 l (11.2%) above baseline after 2 h. Nine of 16 patients showed an increase in FEV1of at least 15% above baseline after zafirlukast. The maximum mean increase in FEV1after zafirlukast in these subjects, who were considered responders, observed after 2 h, was 0.221 (19.4%). The mean difference of post-salbutamol FEV1values after zafirlukast and placebo (−0.036 l) was not significant (P<0.05). In responders, the mean of differences in pre- and post-salbutamol FEV1values after zafirlukast was 0.077 l, whereas the mean of differences between post-salbutamol values after zafirlukast and those after placebo was −0.064 l. The mean AUC0-4 hfor all patients was 0.121 l for placebo and 0.385 l for zafirlukast. The difference between the placebo and zafirlukast AUC0-4 hwas significant (P<0.05). The individual FEV1AUC0-4 hafter zafirlukast were higher than those after placebo in 12 out of 16 patients. These findings suggest that cysteinyl leukotrienes might be one of the causes of persistent bronchoconstriction in COPD, at least in several smokers, but do not confirm the hypothesis that the effects of zafirlukast and salbutamol are independent and additive.