The discrepancy in results from different studies regarding outcome of weaning from mechanical ventilation may be due to several factors such as the differences in patient populations and weaning indexes used. In order to analyze the clinical characteristics and weaning indexes in patients undergoing a 2-h T-piece weaning trial and the relationship between the etiology of acute respiratory failure (ARF) and the outcome of this weaning trial, we prospectively studied 217 patients receiving mechanical ventilation who met standard weaning criteria. Successful weaning occurred in 57.6% (125 of 217) of patients: 13 of 33 (39.4%) patients with chronic obstructive pulmonary disease (COPD), 27 of 46 (58.7%) neurologic patients, and 85 of 138 (61.6%) patients with ARF. Ventilatory support was reinstituted in 31.8% (69 of 217) patients: 20 of 33 (60.6%) of patients with COPD, four of 46 (8.7%) neurologic patients, and 45 of 138 (32.6%) patients with ARF (p < 0.001). Reintubation was required in 23 of 148 (15.5%) patients: 15 of 42 (35.7%) neurologic patients, and eight of 93 (8.6%) patients with ARF, whereas no patient with COPD was reintubated (p < 0.001). Using a discriminant analysis, the following variables were selected as the best predictors of outcome: (1) in the whole population, days of mechanical ventilation before weaning trial (DMV), frequency-to-tidal volume ratio (f/VT), maximal inspiratory pressure (MIP), airway occlusion pressure (P0.1), maximal expiratory pressure (MEP), and vital capacity (VC); (2) in patients with ARF, DMV, P0.1/MIP, MIP, f/VT, and age; (3) in patients with COPD, f/VT, P0.1, P0.1/MIP, MIP, age, and DMV; (4) in neurologic patients, MIP, MEP, and f/VT.P0.1. Using these predictors, 74.6% of the whole population, 76.1% of patients with ARF, 93.9% of patients with COPD, and 73.9% of neurologic patients were accurately classified as weaning successes or failures. The highest rate of reintubation occurred in neurologic patients. In this group, the ability to cough and clear respiratory secretions, objectively reflected by MEP, may help in clinical decision-making.