The objectives of this study were to determine the effect of single and repeat dosing with oral ondansetron, a 5-HT3-specific receptor blocker, on the degree and duration of bronchodilation induced by inhaled ipratropium bromide in patients with COPD. Five clinics and university medical centers in four countries participated in the study; 47 patients with COPD were randomized to treatment; 44 completed all treatments. Patients had a baseline (pre-bronchodilator) FEV1>1L and post-bronchodilator (200 mcg salbutamol) FEV1<90% of predicted, with FEV1 reversibility (to 80 mcg inhaled ipratropium bromide and 400 mcg salbutamol) of at least 12% or 200 mL over baseline. The study was divided into two parts. In Part A, each patient received in a random order, four-way crossover manner, single doses of ondansetron placebo (oral) plus ipratropium bromide placebo (inhaled), ondansetron placebo plus ipratropium bromide 40 mcg inhaled via MDI, ondansetron 24 mg oral plus ipratropium bromide placebo and ondansetron 24 mg plus ipratropium bromide 40 mcg. In Part B, each patient received in a random order, two-way crossover manner, ipratropium bromide 40 mcg tid via MDI plus ondansetron 8 mg oral, qid, for 2 days; on day 3 patients received a single dose of ipratropium bromide 40 mcg plus 8 mg oral ondansetron. Alternatively, patients received ipratropium bromide via MDI and oral ondansetron placebo, as described above. Statistically significant differences in weighted mean FEV1 (0-6h), peak FEV1 and FEV1 determined 6h post-dose were noted comparing ipratropium bromide to placebo. Similar positive results were observed for sGaw and FVC. Addition of ondansetron to ipratropium bromide did not significantly modify values obtained with ipratropium alone. Ipratropium bromide induced a marked bronchodilation, compared to placebo. Addition of ondansetron (single or repeated doses) did not significantly increase the degree or duration of bronchodilation induced by ipratropium alone. sGaw was consistently more sensitive than FEV1 in measuring extent and duration of bronchodilation.