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Abstract Background The chronic and progressive nature of chronic obstructive pulmonary disease (COPD) requires self-administration of inhaled medication. Dry powder inhalers (DPIs) are increasingly being used for inhalation therapy in COPD. Important considerations when selecting DPIs include inhalation effort required and flow rates achieved by patients. Here, we present the comparison of the peak inspiratory flow rate (PIF) values achieved by COPD patients, with moderate to very severe airflow limitation, through the Breezhaler®, the Ellipta® and the HandiHaler® inhalers. The effects of disease severity, age and gender on PIF rate were also evaluated. Methods This randomized, open-label, multicenter, cross-over, Phase IV study recruited patients with moderate to very severe airflow limitation (Global Initiative for Obstructive Lung Disease 2014 strategy), aged ≥40 years and having a smoking history of ≥10 pack years. No active drug or placebo was administered during the study. The inhalation profiles were recorded using inhalers fitted with a pressure tap and transducer at the wall of the mouthpiece. For each patient, the inhalation with the highest PIF value, out of three replicate inhalations per device, was selected for analysis. A paired t-test was performed to compare mean PIFs between each combination of devices. Results In total, 97 COPD patients were enrolled and completed the study. The highest mean PIF value (L/min ± SE) was observed with the Breezhaler® (108 ± 23), followed by the Ellipta® (78 ± 15) and the HandiHaler® (49 ± 9) inhalers and the lowest mean pressure drop values were recorded with the Breezhaler® inhaler, followed by the Ellipta® inhaler and the HandiHaler® inhaler, in the overall patient population. A similar trend was consistently observed in patients across all subgroups of COPD severity, within all age groups and for both genders. Conclusions Patients with COPD were able to inhale with the least inspiratory effort and generate the highest mean PIF value through the Breezhaler® inhaler when compared with the Ellipta® and the HandiHaler® inhalers. These results were similar irrespective of patients’ COPD severity, age or gender. Trial registration The trial was registered with ClinicalTrials.gov NCT02596009 on 4 November 2015.