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Background: High-flow nasal cannula (HFNC) has become a frequently used noninvasive form of respiratory support in acute settings; however, evidence supporting its use has only recently emerged. These guidelines provide evidence-based recommendations for the use of HFNC alongside other noninvasive forms of respiratory support in adults with acute respiratory failure (ARF)., Materials and Methodology: The European Respiratory Society task force panel included expert clinicians and methodologists in pulmonology and intensive care medicine. The task force used the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methods to summarise evidence and develop clinical recommendations for the use of HFNC alongside conventional oxygen therapy (COT) and noninvasive ventilation (NIV) for the management of adults in acute settings with ARF., Results: The task force developed eight conditional recommendations, suggesting the use of 1) HFNC over COT in hypoxaemic ARF; 2) HFNC over NIV in hypoxaemic ARF; 3) HFNC over COT during breaks from NIV; 4) either HFNC or COT in post-operative patients at low risk of pulmonary complications; 5) either HFNC or NIV in post-operative patients at high risk of pulmonary complications; 6) HFNC over COT in nonsurgical patients at low risk of extubation failure; 7) NIV over HFNC for patients at high risk of extubation failure unless there are relative or absolute contraindications to NIV; and 8) trialling NIV prior to use of HFNC in patients with COPD and hypercapnic ARF., Conclusions: HFNC is a valuable intervention in adults with ARF. These conditional recommendations can assist clinicians in choosing the most appropriate form of noninvasive respiratory support to provide to patients in different acute settings., Competing Interests: Conflict of interest: S. Oczkowski reports support for the current manuscript from librarian support services; support for attending meetings and/or travel from ERS, European Society of Intensive Care Medicine and Society of Critical Care Medicine, outside the submitted work. Conflict of interest: B. Ergan has nothing to disclose. Conflict of interest: L. Bos reports grants from the Dutch Lung Foundation (young investigator grant), the Dutch Lung Foundation and Health Holland (public-private partnership grant), the Dutch Lung Foundation (Dirkje Postma Award), IMI COVID19 initiative and Amsterdam UMC fellowship, outside the submitted work. Conflict of interest: M. Chatwin reports lecture fees from ResMed UK, Breas Medical UK, MPR Italy; and since December 2020 has worked part time for Breas Medical as their global clinical specialist, including CAB membership and support for attending meetings and/or travel. Conflict of interest: M. Ferrer has nothing to disclose. Conflict of interest: C. Gregoretti reports consulting fees from Mindray and Air Liquide; lecture fees from Vivisol, Philips and Air Liquide; support for attending meetings and/or travel from Fisher & Paykel; outside the submitted work. Conflict of interest: L. Heunks reports grants from InflaRx; consulting fees from Liberate Medical, USA; speaker fees from Fisher & Paykel and Maquet; outside the submitted work. Conflict of interest: J-P. Frat reports funding, provision of study materials, personal fees for lectures, travels and accommodations expenses reimbursement from Fisher and Paykel Healthcare; personal fees as a member of a scientific board from SOS Oxygene; grants from French Ministry of health; outside the submitted work. Conflict of interest: F. Longhini reports honoraria for a lecture from Draeger; issued patent for a new device for noninvasive ventilation (European patent number 3320941) from Intersurgical SPA; outside the submitted work. Conflict of interest: S. Nava has nothing to disclose. Conflict of interest: P. Navalesi has nothing to disclose. Conflict of interest: A. Ozsancak Uğurlu has nothing to disclose. Conflict of interest: L. Pisani has nothing to disclose. Conflict of interest: T. Renda has nothing to disclose. Conflict of interest: A.W. Thille reports payments for lectures and support for attending meetings and/or travel from Fisher & Paykel; Fisher & Paykel provided the high-flow nasal oxygen equipment and masks for NIV in several randomised clinical trials coordinated by our center. Conflict of interest: J.C. Winck reports webinar fees from Armstrong Medical, Breas, Philips and Nippon Gases; outside the submitted work. Conflict of interest: W. Windisch reports grants from Philips/Respironics/USA, Löwenstein Medical/Germany, VitalAire/Germany and Vivisol/Germany; speaking fees from Philips/Respironics/USA, Löwenstein Medical/Germany and VitalAire/Germany; outside the submitted work. Conflict of interest: T. Tonia acts as ERS Methodologist. Conflict of interest: J. Boyd is an employee of the European Lung Foundation. Conflict of interest: G. Sotgiu has nothing to disclose. Conflict of interest: R. Scala has nothing to disclose., (Copyright ©The authors 2022. 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