Aerosol particle size influences airway drug deposition. Current inhaler devices are inefficient, delivering a heterodisperse distribution of drug particle sizes where at best, 20% reaches the lungs. Monodisperse aerosols are the appropriate research tools to investigate basic aerosol science concepts within the human airways. We hypothesized that engineering such aerosols of albuterol would identify the ideal bronchodilator particle size, thereby optimizing inhaled therapeutic drug delivery. Eighteen stable mild-moderate asthmatics (mean forced expiratory volume in one second (FEV₁) 74.3% predicted) participated in a randomised, double blind, cross-over study design. We used a spinning top aerosol generator to produce monodisperse albuterol aerosols of size 1.5µm, 3µm, 6µm, and placebo, which were inhaled at cumulative doses of 10, 20, 40 and 100µg. Lung function changes and tolerability effects were determined. The larger particles, 6µm & 3µm, were significantly more potent bronchodilators than 1.5µm and placebo aerosols for FEV₁, and forced expiratory flow 25-75% of forced vital capacity. A 20µg dose of the 6µm and 3µm aerosols achieved comparable FEV₁ bronchodilation to 200µg from a metered dose inhaler. No adverse effects were observed in heart rate and plasma potassium The data suggest that in mild-moderate asthmatics there is more than one optimal ₂-agonist bronchodilator particle size, and that these are larger particles in the higher part of the respirable range. Aerosols delivered in monodisperse form can enable large reductions of the inhaled dose without loss of clinical efficacy.