To determine the mechanisms of acute respiratory distress and failure in patients with chronic obstructive pulmonary disease (COPD), we studied 17 ventilator-supported patients who failed a trial of spontaneous breathing and 14 patients who tolerated such a trial and were successfully extubated. Immediately before the weaning trials, maximal inspiratory pressure was not statistically different between the two groups (p = 0.48). On discontinuation of the ventilator, the failure group immediately developed rapid shallow breathing, and higher values of dynamic lung elastance (EdynL) (p < 0.01) and intrinsic positive end-expiratory pressure (PEEPi, p < 0.03) than did the success group. Between the onset and end of the trial, the failure group developed further increases in EdynL (p < 0.0001) and PEEPi (p < 0.0001), and increases in inspiratory resistance (p < 0.009) and inspiratory pressure-time product (PTP) (p < 0.0001). Partitioning of PTP at the end of the trial revealed a 111% increase in the PEEPi component, a 33% increase in the non-PEEPi elastic component, and a 42% increase in the resistive component (all p < 0.0001). Despite the increase in PTP, 13 of the failure patients developed an increase in PaCO2. The product of PTP and PaCO2, an index of inefficient CO2 clearance, was more than twice as high in the failure group than in the success group at the end of the trial (p < 0.0005). Thus, development of acute respiratory distress during a failed weaning attempt was due to worsening of pulmonary mechanics, which in conjunction with rapid shallow breathing led to inefficient clearance of CO2.