Rationale: Aerosol particle size influences the extent, distribution and site of inhaled drug deposition within the airways. Objectives: We hypothesized that targeting albuterol to regional airways by altering aerosol particle size could optimize inhaled bronchodilator delivery. Methods: In a randomized, double-blind, placebo-controlled study, 12 asthmatic subjects (FEV₁ 76.8±11.4% predicted) inhaled technetium-99m-labeled monodisperse albuterol aerosols (30µg-dose)of 1.5µm, 3µm, and 6µm mass median aerodynamic diameter, at slow (30-60 l/min) and fast (>60 l/min) inspiratory flows. Lung and extrathoracic radioaerosol deposition were quantified using planar gamma-scintigrapy. Pulmonary function and tolerability measurements were simultaneously assessed. Clinical efficacy was also compared with unlabeled monodisperse albuterol (15µg-dose) and 200µg MDI albuterol. Results: Smaller particles achieved greater total lung deposition: 1.5µm(56%), 3µm(50%), 6µm(46%), further distal airways penetration (0.79, 0.60, 0.36, respective penetration index), and more peripheral lung deposition (25%, 17%, 10%, respectively). However, larger particles (30µg-dose) were more efficacious, and achieved greater bronchodilation than 200µg MDI albuterol; FEV₁(ml); 6µm(551), 3µm(457), 1.5µm(347), MDI(494). Small particles were exhaled more 1.5µm(22%), 3µm(8%), 6µm(2%), whereas greater oropharyngeal deposition occurred with large particles (15%, 31%, 43%, respectively). Faster inspiratory flows decreased total lung deposition and increased oropharyngeal deposition for the larger particles with less bronchodilation. A shift in aerosol distribution to the proximal airways was observed for all particles. Conclusions: Regional targeting of inhaled ₂-agonist to the proximal airways is more important than distal alveolar deposition for bronchodilation. Altering intrapulmonary deposition through aerosol particle size can appreciably enhance inhaled drug therapy and may have implications for developing future inhaled treatments.