BACKGROUND: High-flow nasal cannula use is developing in ICUs. The aim of this study was to compare aerosol efficiency by using two nebulizers through a high-flow nasal cannula: the most commonly used jet nebulizer (JN) and a more efficient vibrating-mesh nebulizer (VN). METHODS: Aerosol delivery of diethylenetriaminepentaacetic acid labeled with technetium-99m (4 mCi/4 mL) to the lungs by using a VN (Aerogen Solo((R)); Aerogen Ltd., Galway, Ireland) and a constant-output JN (Opti-Mist Plus Nebulizer((R)); ConvaTec, Bridgewater, NJ) through a high-flow nasal cannula (Optiflow((R)); Fisher & Paykel, New Zealand) was compared in six healthy subjects. Flow rate was set at 30 L/min through the heated humidified circuit. Pulmonary and extrapulmonary deposition was measured by single-photon emission computed tomography combined with a low-dose computed tomographic scan and by planar scintigraphy. RESULTS: Lung deposition was only 3.6 (2.1-4.4) and 1 (0.7-2)% of the nominal dose with the VN and the JN, respectively (p < 0.05). The JN showed higher retained doses than the VN. However, both nebulizers were associated with substantial deposition in the single limb circuit, the humidification chamber, and the nasal cannula [58.2 (51.6-61.6)% of the nominal dose with the VN versus 19.2 (15.8-22.9)% of the nominal dose with the JN, p < 0.05] and in the upper respiratory tract [17.6 (13.4-27.9)% of the nominal dose with the VN and 8.6 (6.0-11.0)% of the nominal dose with the JN, p < 0.05], especially in the nasal cavity. CONCLUSIONS: In the specific conditions of the study, pulmonary drug delivery through the high-flow nasal cannula is about 1%-4% of the initial amount of drugs placed in the nebulizer, despite the higher efficiency of the VN as compared with the JN.