We investigated the prognostic utility of changes in N-terminal pro-brain natriuretic peptide (NT-proBNP) in combination with Sequential Organ Failure Assessment (SOFA) score in patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) concomitant with septic shock. Forty-nine mechanically ventilated patients with ALI/ARDS concomitant with septic shock were studied. N-terminal pro-brain natriuretic peptide levels were measured on the first 3 days (days 0, 1, and 2) in the intensive care unit. The median NT-proBNP levels in survivors and nonsurvivors were 3,999 vs. 2,819 pg/mL on day 0 (P = 0.719); 4,495 vs. 5,397 pg/mL on day 1 (P = 0.543); and 2,325 vs. 14,173 pg/mL on day 2 (P = 0.028). N-terminal pro-brain natriuretic peptide levels increased significantly from baseline values in nonsurvivors only. We observed a monotonic increase in 28-day mortality associated with increasing quartiles of percent change in NT-proBNP on day 2 (P < 0.0001). Kaplan-Meier survival analysis revealed that mortality was significantly higher in patients with a change in NT-proBNP of 30% or more (log-rank P < 0.0001). On day 2, areas under the receiver operating characteristic curves for predicting 28-day mortality were 0.74 for SOFA alone and 0.85 (P = 0.028) for SOFA combined with percent change in NT-proBNP. In conclusion, in patients with ALI/ARDS concomitant with septic shock, a rising trend (high percent change) in NT-proBNP levels had better prognostic utility than absolute levels. The combination of percent change in NT-proBNP with SOFA may provide superior prognostic accuracy to SOFA alone.