The pressurized metered dose inhaler (pMDI) is a versatile inhalation device that is well-accepted but used incorrectly by many patients. In order to support the development of pMDI therapies and add-on devices, there is an increasing awareness of the regulatory need to simulate the clinical use of inhalers in analytical methodologies, rather than rely on quality control laboratory tools. The aims of this study were two-fold: (1) to develop an experimental approach to simulate the ‘open-mouth’ inhalation technique recommended by many clinicians; and (2) to assess the impact of the open-mouth technique on aerosolization performance for a suspension pMDI of fluticasone propionate (FP, Flixotide 250 µg Evohaler). Employing the open-mouth set-up revealed a significant reduction in recovered dose (from 1177.1 ± 18.5 to 363.9 ± 77.3 µg FP) due to losses to the open environment. Although the open-mouth technique was associated with an excellent reduction in potential throat deposition, there was also a decrease in the fine particle dose from 92.1 ± 1.4 µg to 65.2 ± 22.2 µg (with good alignment of the inhaler with the vertical axis of the induction port) and 28.3 ± 10.1 µg (with a subtle misalignment of the inhaler with the induction port ). The open-mouth technique also resulted in high variability in the performance metrics, which raises concerns over the ability of patients to employ the technique correctly without compromising drug delivery performance. This work has identified the key experimental parameters required to examine the impact of the open-mouth inhalation practised by many patients and provides a benchmark for appropriate in vitro equivalence testing of inhalation devices.