Abstract Introduction Physiological determinants of weaning success and failure are usually studied in ventilator-supported patients, comparing those who failed a trial of spontaneous breathing with those who tolerated such a trial and were successfully extubated. A major limitation of these studies was that the two groups may be not comparable concerning the severity of the underlying disease and the presence of comorbidities. In this physiological study, we assessed the determinants of weaning success in patients acting as their own control, once they are eventually liberated from the ventilator. Methods In 30 stable tracheotomised ventilator-dependent patients admitted to a weaning center inside a respiratory intensive care unit, we recorded the breathing pattern, respiratory mechanics, inspiratory muscle function, and tension-time index of diaphragm (TTdi = Pdisw/Pdi max [that is, tidal transdiaphragmatic pressure over maximum transdiaphragmatic pressure] × Ti/Ttot [that is, the inspiratory time over the total breath duration]) at the time of weaning failure (T 0 ). The measurements were repeated in all the patients (T 1 ) either during a successful weaning trial (successful weaning [SW] group, n = 16) or 5 weeks later, in the case of repeated weaning failure (failed weaning [FW] group, n = 14). Results Compared to T 0 , in the FW group at T 1 , significant differences were observed only for a reduction in spontaneous breathing frequency and in TTdi (0.21 ± 0.122 versus 0.14 ± 0.054, P = 0.008). SW patients showed a significant increase in Pdi max (34.9 ± 18.9 cm H 2 O versus 43.0 ± 20.0, P = 0.02) and decrease in Pdisw/Pdi max (36.0% ± 15.8% versus 23.1% ± 7.9%, P = 0.004). Conclusions The recovery of an inadequate inspiratory muscle force could be the major determinant of 'late' weaning success, since this allows the patients to breathe far below the diaphragm fatigue threshold.