We used an in vitro model system to examine the sites of deposition of aqueous therapeutic aerosols administered through 3-mm, 6-mm, and 9-mm endotracheal tubes (commonly used in infants, children, and adults) at clinically relevant inspiratory flow rates. Aerosol was delivered to the endotracheal tube via a "T" piece and a 90 degree elbow. Aerosol exiting the endotracheal tube passed through an appropriately sized Plexiglas model of the trachea and mainstem bronchi, and then into an 80-liter bag. Aerosol deposited in the "T" and elbow, endotracheal tube, large airway model, and collection bag was quantitated separately using 0.1% uranine as a tracer. Study of a conventional aerosol typical of those in common clinical use (aerodynamic mass median diameter = 3.95 microns) showed that most of the aerosol delivered into each endotracheal tube was deposited before leaving the mainstem bronchi. Substitution of an alternative nebulizer that produced a much smaller aerosol particle size (aerodynamic mass median diameter = 0.54 micron) dramatically decreased aerosol deposition in the "T" and elbow, endotracheal tube, and large airway model, and increased the quantity of aerosol penetrating beyond the mainstem bronchi up to ninefold. The mass median particle diameter of the conventional aerosol was reduced during endotracheal tube and large airway passage by poorly defined aerodynamic mechanisms that selectively removed larger particles. The smaller submicron aerosol was not similarly affected. Thus, conventional therapeutic aerosols appear to penetrate poorly through endotracheal tubes. Use of smaller particle size aerosols in treatment of intubated patients may be an effective way to circumvent this problem.