BackgroundPatients liberated from invasive mechanical ventilation are at risk of extubation failure, including inability to breathe without a tracheal tube (airway failure) or without mechanical ventilation (non-airway failure). We sought to identify respective risk factors for airway failure and non-airway failure following extubation.MethodsThe primary endpoint of this prospective, observational, multicenter study in 26 intensive care units was extubation failure, defined as need for reintubation within 48 h following extubation. A multinomial logistic regression model was used to identify risk factors for airway failure and non-airway failure.ResultsBetween 1 December 2013 and 1 May 2015, 1514 patients undergoing extubation were enrolled. The extubation-failure rate was 10.4% (157/1514), including 70/157 (45%) airway failures, 78/157 (50%) non-airway failures, and 9/157 (5%) mixed airway and non-airway failures. By multivariable analysis, risk factors for extubation failure were either common to airway failure and non-airway failure: intubation for coma (OR 4.979 (2.797–8.864), P < 0.0001 and OR 2.067 (1.217–3.510), P = 0.003, respectively, intubation for acute respiratory failure (OR 3.395 (1.877–6.138), P < 0.0001 and OR 2.067 (1.217–3.510), P = 0.007, respectively, absence of strong cough (OR 1.876 (1.047–3.362), P = 0.03 and OR 3.240 (1.786–5.879), P = 0.0001, respectively, or specific to each specific mechanism: female gender (OR 2.024 (1.187–3.450), P = 0.01), length of ventilation > 8 days (OR 1.956 (1.087–3.518), P = 0.025), copious secretions (OR 4.066 (2.268–7.292), P < 0.0001) were specific to airway failure, whereas non-obese status (OR 2.153 (1.052–4.408), P = 0.036) and sequential organ failure assessment (SOFA) score ≥ 8 (OR 1.848 (1.100–3.105), P = 0.02) were specific to non-airway failure. Both airway failure and non-airway failure were associated with ICU mortality (20% and 22%, respectively, as compared to 6% in patients with extubation success, P < 0.0001).ConclusionsSpecific risk factors have been identified, allowing us to distinguish between risk of airway failure and non-airway failure. The two conditions will be managed differently, both for prevention and curative strategies.Trial registrationClinicalTrials.gov, NCT 02450669. Registered on 21 May 2015. Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2150-6) contains supplementary material, which is available to authorized users.