Recent studies show that nasal high flow (NHF) therapy can support ventilation in patients with acute or chronic respiratory disorders. Clearance of dead-space has been suggested as being the key mechanisms of respiratory support with NHF therapy. The hypothesis of this study was that NHF in a dose-dependent manner can clear dead space of the upper airways from expired air and decrease re-breathing. The randomized cross-over study involved 10 volunteers using scintigraphy with 81mKrypton-gas (81mKr-gas) during a breath-holding maneuver with closed mouth and in three nasally breathing tracheotomized patients by volumetric capnography and oximetry through sampling CO2 and O2 in the trachea and measuring the inspired volume with inductance plethysmography following NHF rates of 15, 30 and 45 L/min. The scintigraphy revealed a decrease in 81mKr-gas clearance half-time with an increase of NHF in the nasal cavities (cc = -0.55, p < 0.01), pharynx (cc = -0.41, p < 0.01) and the trachea (cc = -0.51, p < 0.01). Clearance rates in nasal cavities derived from time constants and MRI-measured volumes were 40.6 (SD 12.3), 52.5 (SD 17.7) and 72.9 (SD 21.3) mL/s during NHF (15-30-45L/min). Measurement of inspired gases in the trachea showed an NHF-dependent decrease of inspired CO2 that correlated with an increase of inspired O2 (cc = -0.77, p < 0.05). NHF clears the upper airways from expired air, which reduces dead space by a decrease of re-breathing making ventilation more efficient. The dead-space clearance is flow and time-dependent and it may extend below the soft palate.