For this article, we studied the effects of mouthpiece diameter and flow rate on aerosol penetration efficiency for metered-dose inhaler (MDI) applications. Measurements show that increasing the mouthpiece diameter has a moderate and positive influence on the particle penetration efficiency of the MDI. The particle penetration efficiency increases monotonically with the increase of the mouthpiece diameter from 16 mm to 20 mm. Second, the experiments show that airflow rate has an apparent and significant effect on particles deposition in the oral airway. The reduction of the airflow rate from 90 L/min to 30 L/min tripled the penetration efficiency of the MDI. A new experimental system has been employed to measure the particles deposition in the human airways. Expansion balloons were used to induce airflow as well as to collect the penetrated particles through an airway cast. The potential advantages of the balloon-based experimental system are simplicity, accuracy, and cost-effectiveness.