Previous studies have shown that spontaneous breathing trials (SBT) with a T-tube or low-level pressure support are comparable. However, low-level pressure support may overestimate the ability of a patient to sustain spontaneous breathing, resulting in premature extubation. Understanding factors contributing to different responses by patients to the two SBT methods aids in clarifying the limitation of using low-level pressure support for SBT. We performed a prospective observational study in 80 consecutive adult patients with mechanical ventilation to identify the factors contributing to different responses of a patient to the two SBT methods. The 80 patients underwent both a T-tube trial and pressure support ventilation of 6 cmH2O (PS-6) on the day of extubation. Stratified analysis was used to evaluate the effects of age, respiratory compliance and resistance, PaO2/FiO2 ratio and underlying disease on post-SBT responses. Comparing the responses to a T-tube trial and PS-6, the patients with old age, poor pulmonary compliance (≤40 ml/cmH2O) and chronic obstructive pulmonary disease had a higher heart rate (difference [95% CI]: 4 [0,8], 5 [2,9], 5 [0,10] beats/minute, respectively) and systolic blood pressure (10 [4,16], 11 [5,16], 7 [0,13] mmHg, respectively) after the T-tube trial. In conclusion, this research shows that old age and impaired respiratory mechanics contribute to different responses to spontaneous breathing trials with a T-tube and low-level pressure support. Further studies are needed to compare the effectiveness of the two SBT methods in predicting successful extubation in such patient groups.