Aerosolized recombinant human DNase (dornase alfa) reduces mucus viscoelasticity in vitro and improves pulmonary function in patients with cystic fibrosis (CF). We postulated that if dornase alfa could be delivered more peripherally to small airways in the lung in the form of smaller aerosol droplets in patients with early airway obstruction, the increase in pulmonary function from baseline might be improved. CF patients (n = 749) with mild lung disease (baseline forced vital capacity > or = 70% predicted) were randomly assigned to receive dornase alfa 2.5 mg daily for 2 weeks by one of two nebulizer systems: 1) the Medic-Aid Durable SideStream nebulizer powered by the MobilAire Compressor (SS/MA) producing a droplet size with a mass median aerodynamic diameter (MMAD) of 2.1 microm; or 2) the Hudson T Up-draft nebulizer with a DeVilbiss Pulmo-Aide compressor (HT/PA) with an MMAD of 4.9 microm. Spirometry was performed at baseline and following 14 days of treatment. Dornase alfa delivered by both nebulizer systems produced small but statistically significant improvements in pulmonary function compared with baseline. There was a trend (P = 0.06) toward greater improvement in forced expiratory flow in 1 s in the SS/MA group (4.3%) compared with the HT/PA group (2.5%). These results indicate that the short-term spirometric response to dornase alfa is influenced in part by the physical characteristics of the aerosol in patients with mild lung disease. We speculate that this may be true for other therapeutic aerosols, and it appears that localization of disease in the lung plays a role in the response to inhaled agents.