BACKGROUND: Combining bronchodilators has been shown to be beneficial in patients with COPD. The additive effects of short-acting bronchodilators added to maintenance tiotropium therapy, however, are unknown. METHODS: Following 3 weeks of tiotropium pretreatment, 60 patients with COPD (FEV1 40% of predicted) participated in a randomized, placebo-controlled study to assess add-on bronchodilator effects of ipratropium bromide (40 microg) or fenoterol (200 microg). Short-acting bronchodilators were added as a single dose 2 h and 8 h after tiotropium dosing. Serial lung function tests were performed over 9 h. RESULTS: The peak FEV1 add-on response within 6 h with fenoterol was significantly greater than with placebo (137 mL) or ipratropium (84 mL); the response with ipratropium was slightly but significantly larger than with placebo (52 mL). One hour after the second dose of the test drugs, a similar order of treatment responses was found. The peak FVC add-on response was significant for fenoterol (249 mL) but not for ipratropium (42 mL). CONCLUSIONS: In conclusion, both short-acting bronchodilator classes were effective when added to maintenance treatment with tiotropium. The addition of the beta2-adrenergic fenoterol provided greater additional bronchodilatation than the short-acting anticholinergic ipratropium. This is consistent with the expected effects of combining bronchodilators with different pharmacologic mechanisms. This randomized controlled trial was registered at www.clinicaltrials.gov (NCT00274066).