We have previously shown (Am. J. Respir. Crit. Care Med. 1995;152:1248-1255) that in patients needing mechanical ventilation, the load imposed on the inspiratory muscles is excessive relative to their neuromuscular capacity. We have therefore hypothesized that weaning failure may occur because at the time of the trial of spontaneous breathing there is insufficient reduction of the inspiratory load. We therefore prospectively studied patients who initially had failed to wean from mechanical ventilation (F) but had successful weaning (S) on a later occasion. Compared with S, during F patients had greater intrinsic positive end-expiratory pressure (6. 10 +/- 2.45 versus 3.83 +/- 2.69 cm H2O), dynamic hyperinflation (327 +/- 180 versus 213 +/- 175 ml), total resistance (Rmax, 14.14 +/- 4.95 versus 11.19 +/- 4.01 cm H2O/L/s), ratio of mean to maximum inspiratory pressure (0.46 +/- 0.1 versus 0.31 +/- 0.08), tension time index (TTI, 0.162 +/- 0.032 versus 0.102 +/- 0.023) and power (315 +/- 153 versus 215 +/- 75 cm H2O x L/min), less maximum inspiratory pressure (42.3 +/- 12.7 versus 53.8 +/- 15.1 cm H2O), and a breathing pattern that was more rapid and shallow (ratio of frequency to tidal volume, f/VT 98 +/- 38 versus 62 +/- 21 breaths/min/L). To clarify on pathophysiologic grounds what determines inability to wean from mechanical ventilation, we performed multiple logistic regression analysis with the weaning outcome as the dependent variable. The TTI and the f/VT ratio were the only significant variables in the model. We conclude that the TTI and the f/VT are the major pathophysiologic determinants underlying the transition from weaning failure to weaning success.