Knowledge on the effects of the additive bronchodilatory effects of short-acting agents on the top of the effect of long-acting bronchodilators is limited. In this trial, we examined the influence of higher than conventional doses of the short-acting inhaled beta(2)-adrenergic agent salbutamol and the short-acting anticholinergic drug ipratropium bromide on bronchodilation induced by a regular treatment with the long-acting anticholinergic drug tiotropium 18 microg/day in 30 patients with stable COPD. On 3 separate days, a dose-response curve to inhaled salbutamol (100 microg puff-1), ipratropium bromide (20 microg puff-1) or placebo was constructed 3h after inhalation of the last dose of tiotropium, using one puff, one puff, two puffs and two puffs, for a total cumulative dose of 600 microg salbutamol or 120 microg ipratropium bromide. Doses were given at 30-min intervals and measurements made 15 min after each dose. At the highest cumulative dose, salbutamol showed a trend to be more effective than ipratropium bromide in improving FEV(1) (0.157 L vs 0.125 L), and reducing sRaw (-4.52 kPa/s vs 3.57 kPa/s), although the differences between the two treatments were always not significant (p>0.05), whereas there was no substantial difference between the two drugs in changing FVC (0.179 L vs 0.168 L), IC (0.254 L vs 0.240 L), TGV (-0.444 L vs -0.441 L), TLC (-0.334 L vs -0.318 L) and RV (-0.467 L vs -0.498 L). Both drugs did not affect heart rate and SpO2. Our results indicate that there is not much difference in bronchodilation between adding higher than conventional doses of salbutamol or ipratropium bromide to tiotropium in patients with stable COPD. Effective improvement of the pulmonary function may be achieved in such a type of patients by adding salbutamol 600 microg or ipratropium bromide 120 microg to regular tiotropium. These is an interesting finding mainly for those COPD patients suffering from cardiovascular co-morbidities that are at highest risk of myocardial infarction, congestive heart failure, cardiac arrest and sudden cardiac death when treated with elevated doses of a beta(2)-agonist (EudraCT number: 2007-001597-82).