Abstract Introduction Tolerance of a spontaneous breathing trial is an evidence-based strategy to predict successful weaning from mechanical ventilation. Some patients may not tolerate the trial because of the respiratory load imposed by the endotracheal tube, so varying levels of respiratory support are widely used during the trial. Automatic tube compensation (ATC), specifically developed to overcome the imposed work of breathing because of artificial airways, appears ideally suited for the weaning process. We further evaluated the use of ATC in this setting. Methods In a prospective study, patients who had received mechanical ventilation for more than 24 hours and met defined criteria for a weaning trial, underwent a one-hour spontaneous breathing trial with either ATC (n = 87) or pressure support ventilation (PSV; n = 93). Those tolerating the trial were immediately extubated. The primary outcome measure was the ability to maintain spontaneous, unassisted breathing for more than 48 hours after extubation. In addition, we measured the frequency/tidal volume ratio (f/VT) both with (ATC-assisted) and without ATC (unassisted-f/VT) at the start of the breathing trial as a pretrial predictor of extubation outcome. Results There were no significant differences in any of the baseline characteristics between the two groups apart from a significantly higher Acute Physiology and Chronic Health Evaluation (APACHE) II score in the ATC group (p = 0.009). In the PSV group, 13 of 93 (14%) patients failed the breathing trial compared with only 6 of 87 (6%) in the ATC group; this observed 8% difference, however, did not reach statistical significance (p = 0.12). The rate of reintubation was not different between the groups (total group = 17.3%; ATC = 18.4% vs. PSV = 12.9%, p = 0.43). The percentage of patients who remained extubated for more than 48 hours was similar in both groups (ATC = 74.7% vs. PSV = 73.1%; p = 0.81). This represented a positive predictive value for PSV of 0.85 and ATC of 0.80 (p = 0.87). Finally, the ATC-assisted f/VT was found to have a significant contribution in predicting successful liberation and extubation compared with the non-significant contribution of the unassisted f/VT (unassisted f/VT, p = 0.19; ATC-assisted f/VT, p = 0.005). Conclusions This study confirms the usefulness of ATC during the weaning process, being at least as effective as PSV in predicting successful extubation outcome and significantly improving the predictive value of the f/VT. Trial registration Current Controlled Trials ISRCTN16080446