Abstract Background Many patients with asthma require frequent rescue medication for acute symptoms despite appropriate controller therapies. Thus, determining the most effective relief regimen is important in the management of more severe asthma. This study’s objective was to evaluate whether ipratropium bromide/albuterol metered-dose inhaler (CVT-MDI) provides more effective acute relief of bronchospasm in moderate-to-severe asthma than albuterol hydrofluoroalkaline (ALB-HFA) alone after 4 weeks. Methods In this double-blind, crossover study, patients who had been diagnosed with asthma for ≥1 year were randomized to two sequences of study medication “as needed” for symptom relief (1–7 day washout before second 4-week treatment period): CVT-MDI/ALB-HFA or ALB-HFA/CVT-MDI. On days 1 and 29 of each sequence, 6-hour serial spirometry was performed after administration of the study drug. Co-primary endpoints were FEV 1 area under the curve (AUC 0–6 ) and peak (post-dose) forced expiratory volume in 1 s (FEV 1 ) response (change from test day baseline) after 4 weeks. The effects of “as needed” treatment with ALB-HFA/CVT-MDI were analyzed using mixed effect model repeated measures (MMRM). Results A total of 226 patients, ≥18 years old, with inadequately controlled, moderate-to-severe asthma were randomized. The study met both co-primary endpoints demonstrating a statistically significant treatment benefit of CVT-MDI versus ALB-HFA. FEV 1 AUC 0-6h response was 167 ml for ALB-HFA, 252 ml for CVT-MDI ( p