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Background: The bronchodilator response to short-acting β2-agonist and short-acting muscarinic antagonist monotherapies varies on a day-to-day basis within individual patients. The objective of this study was to compare daily variation in bronchodilator response to the combined use of albuterol and ipratropium with monotherapies in patients with chronic obstructive pulmonary disease (COPD)., Methods: This was a 4-week, randomized, open-label, two-period crossover study in patients with COPD. Patients were randomized 1:1 to receive albuterol via metered dose inhaler followed by ipratropium or vice versa during treatment Period 1 (10-14 days). The order of treatments was then reversed during treatment Period 2 (10-14 days). Pre-defined efficacy endpoints were: forced expiratory volume in 1 s (FEV1), derived FEV1, inspiratory capacity (IC) and daily variability of FEV1 and IC as measured by coefficient of variation (CV)., Results: Albuterol and ipratropium improved FEV1 when administered as the first bronchodilator, compared with pre-dose values (0.269 and 0.243 L, respectively). Administration of the second bronchodilator provided further improvements in lung function, but to a lesser magnitude than the first bronchodilator (0.094 L for both treatments). A statistically significant reduction in daily variability in FEV1 was observed for dual bronchodilator therapy compared with monotherapy (difference in CV = 0.007; p = 0.019) and pre-dose values (no treatment; difference in CV = 0.022; p < 0.001)., Conclusions: The free combination of albuterol and ipratropium resulted in greater improvements and lower day-to-day variability in FEV1 compared with either monotherapy or no bronchodilator therapy. The reduced daily variability may be an important therapeutic advantage of using different classes of bronchodilators in COPD., Trial Registration: NCT01691482., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)