Objective To evaluate the effect of high flow nasal catheter oxygen (HFNCO) therapy on extubation failure rate, reintubation rate, and incidence of related complications within 48 h after extubation in mechanically ventilation patients. Methods A prospective, single-center, randomized controlled trial was conducted in the ICU of a teaching hospital affiliated to a medical university. A total of 77 patients with mechanical ventilation duration of≥ 48 h and met the condition of spontaneous breathing test (SBT) were selected. The patients whose LUS≥14 at 30 min of SBT were enrolled, and were randomly (random number) divided into 3 groups according to different oxygen therapies: the traditional oxygen therapy group, the noninvasive ventilation (NIV) group, and the HFNCO group. The effect of oxygen therapy and outcomes after extubation were compared among the three groups. The measurement data were presented as the mean±standard deviation (SD), and the numeration data were expressed as ratio or constituent ratio. The independent sample t test and LSD-t test were used for the comparisons between the two groups and the one-way ANOVA for differences between multiple groups. The differences between enumeration data were assessed by chi-square test. A P<0.05 was considered statistically significant. Results There was no significant difference in gender, age and other general conditions between the two groups (P>0.05). The NIV group and HFNCO group had lower extubation failure rate (14.29%, 15.38% vs 34.87%) and reintubation rate (10.7%, 11.54% vs 21.74%) than the conventional oxygen therapy group (P<0.05). In addition, the traditional oxygen therapy group had longer mechanical ventilation duration [(24.33±4.42) d vs (8.58±1.09) d, (8.37±2.43) d], antibiotic use time [(19.21±4.37) d vs (8.34±2.54) d, (7.41±1.06) d], and ICU hospitalization time [(27.27±4.24) d vs (10.38±2.07) d, (9.44±0.79) d], all P<0.05. Conclusions Treatment with HFNCO or NIV after extubation can effectively reduce the rates of extubation failure and reintubation, and improve the outcome of the mechanical ventilation. There is no difference in clinical efficiency between the NIV group and HFNCO group. However, compared with NIV, HFNCO can effectively reduce respiratory rate and avoid the retention of CO2, which has a wider application prospect in clinical practice. Key words: Pulmonary ultrasound; Mechanical ventilation; Extubation; High flow nasal catheter oxygen therapy