Oxygenation through High Flow Delivery Systems (HFO) is described as capable of delivering accurate F. Meanwhile, peak inspiratory flow [Formula: see text] ) of patients with acute hypoxemic respiratory failure can reach up to 120 L/min, largely exceeding HFO flow. Currently, very few data on the reliability of HFO devices at these high [Formula: see text] are available. We sought to evaluate factors affecting oxygenation while using HFO systems at high [Formula: see text] in a bench study. Spontaneous breathing was generated with a mechanical test lung connected to a mechanical ventilator Servo-i®, set to volume control mode. Gas flow from a HFO device was delivered to the test lung. The influence on effective inspired oxygen fraction of three parameters (F 0.6, 0.8, and 1, [Formula: see text] from 28 to 98.1 L/min, and HFO Gas Flows from 40 to 60 L/min) were analyzed and are reported. The present bench study demonstrates that during HFO treatment, measured F in the lung does not equal set F on the device. The substance of this variation (ΔF) is tightly correlated to [Formula: see text] (Pearson's coefficient of 0.94, p-value < 0.001). Additionally, set F and Flow at HFO device appear to significatively affect ΔF as well (p-values < 0.001, adjusted to [Formula: see text] ). The result of multivariate linear regression indicates predictors ([Formula: see text] , Flow and set F) to explain 92% of the variance of delta F through K-Fold Cross Validation. Moreover, adjunction of a dead space in the breathing circuit significantly decreased ΔF (p < 0.01). The present bench study did expose a weakness of HFO devices in reliability of delivering accurate F at high [Formula: see text] as well as, to a lesser extent, at [Formula: see text] below equivalent set HFO Flows. Moreover, set HFO flow and set F did influence the variability of effective inspired oxygen fraction. The adjunction of a dead space in the experimental set-up significantly amended this variability and should thus be further studied in order to improve success rate of HFO therapy.