Few studies have investigated the measurement of oxygen uptake ([Formula: see text]O2) in tracheostomized patients undergoing unassisted breathing trials (UBTs) for liberation from mechanical ventilation (MV). Using an open-circuit, breath-to-breath method, we continuously measured [Formula: see text]O2 and relevant parameters during 120-min UBTs via a T-tube in 49 tracheostomized patients with prolonged MV, and calculated mean values in the first and last 5-min periods. Forty-one (84%) patients successfully completed the UBTs. The median [Formula: see text]O2 increased significantly (from 235.8 to 298.2 ml/min; P = 0.025) in the failure group, but there was no significant change in the success group (from 223.1 to 221.6 ml/min; P = 0.505). In multivariate logistic regression analysis, an increase in [Formula: see text]O2 > 17% from the beginning period (odds ratio [OR] 0.084; 95% confidence interval [CI] 0.012-0.600; P = 0.014) and a peak inspiratory pressure greater than - 30 cmH2O (OR 11.083; 95% CI 1.117-109.944; P = 0.04) were significantly associated with the success of 120-min UBT. A refined prediction model combining heart rate, energy expenditure, end-tidal CO2 and oxygen equivalent showed a modest increase in the area under the receiver operating characteristic curve of 0.788 (P = 0.578) and lower Akaike information criterion score of 41.83 compared to the traditional prediction model including heart rate and respiratory rate for achieving 48 h of unassisted breathing. Our findings show the potential of monitoring [Formula: see text]O2 in the final phase of weaning in tracheostomized patients with prolonged MV.