Background: Oxygen therapy is required to prevent hypoxemia during the endobronchial ultrasonography(EBUS) procedure.Aims: We aimed to compare the effectiveness of oxygen therapy delivered via high-flow nasal cannula(HFNC) and conventional nasal cannula(CNC) in patients undergoing EBUS. Primary outcome was proportion of the patients who desaturated. Patient compliance and satisfaction were also evaluated.Methods: This single-center prospective interventional study was conducted in a tertiary hospital among patients who presented to the EBUS unit in 2018 and 2019. Patients were randomly assigned to the HFNC group or the CNC group.Results: The study included 170 patients (111 men and 59 women) with a mean age of 58 ± 14 years. The number of patients experiencing desaturation while receiving oxygen was statistically significantly lower (P < 0.001) in HFNC group (n = 5) compared with CNC group (n = 26). Oxygen therapy was adjusted in 2 patients in the CNC group due to desaturation. Saturation was significantly higher in the HFNC group (P < 0.0001) at the end of the EBUS procedure. HR at the end of EBUS was lower in the HFNC group, but this difference was not statistically significant (96 ± 16 vs. 101 ± 19, P = 0.13). Five patients in the HFNC group and 18 patients in the CNC group reported discomfort during the procedure (P = 0.006).Conclusion: Oxygen therapy delivered by HFNC seems to be safer and more effective than by CNC in patients undergoing EBUS. Oxygen therapy with HFNC may be considered as an alternative to CNC because it may increase patient comfort and thereby improve compliance. This article is protected by copyright. All rights reserved.