The determinants of barotrauma in mechanically ventilated patients with acute lung injury or acute respiratory distress syndrome (ALI/ARDS) have not been clearly established. Using data from ARDS Network randomized controlled trials, we retrospectively examined the association between airway pressures and the risk of early barotrauma in a cohort of 718 patients with ALI/ARDS and no baseline barotrauma. We studied airway pressures at three exposure intervals: baseline, one day preceding the barotrauma event (one-day lag), and concurrent with the barotrauma event. During the first four study days, the cumulative incidence of barotrauma was 13% (95% confidence interval [CI] 10.6 to 15.6%). In a forward stepwise Cox proportional hazards analysis using time-dependent variables, higher concurrent positive end-expiratory pressure (PEEP) was associated with an increased risk of early barotrauma (relative hazard [RH] 1.67 per 5-cm H2O increment; 95% CI 1.35-2.07). Once concurrent PEEP was selected into the model, no other airway pressure was related to barotrauma, including plateau pressure. In the multivariate analysis, higher concurrent PEEP was also related to a greater risk of barotrauma (RH 1.93; 95% CI 1.44-2.60), controlling for age, ventilator group (6 versus 12 ml/kg), baseline PEEP, baseline plateau pressure, baseline tidal volume, Acute Physiology and Chronic Health Evaluation score, vasopressor use, serum albumin, hepatic failure, and coagulopathy. When one-day lagged values of PEEP were analyzed, higher PEEP was associated with a greater risk of barotrauma (RH 1.38 per 5-cm H2O increment; 95% CI 1.09-1.76). Controlling for the covariates, higher PEEP was related to an increased risk of barotrauma (RH 1.50; 95% CI 0.98- 2.30). In conclusion, higher PEEP may increase the likelihood of early barotrauma in ALI/ARDS.