Objective: In acute lung injury, lung overinflation resulting from mechanical ventilation with positive end-expiratory pressure (PEEP) can be assessed using lung computed tomography. The goal of this study was to compare lung overinflation measured on low and high spatial resolution computed tomography sections. Design: Lung overinflation was measured on thick (10-mm) and thin (1.5-mm) computed tomography sections obtained at zero end-expiratory pressure (ZEEP) and PEEP 10 cm H2O using a software including a color-coding system. Setting: A 20-bed surgical intensive care unit of a university hospital. Patients: Thirty mechanically ventilated patients with acute lung injury. Interventions: None. Measurements and Main Results: Overinflated lung volume was measured as the end-expiratory volume of lung regions with computed tomography attenuations < 900 Hounsfield units. Lung overinflation, expressed in percentage of the total lung volume, was significantly underestimated by thick computed tomography sections compared with thin computed tomography sections (0.4 1.6% vs. 3.0 4.0% in ZEEP and 1.9 4% vs. 6.8 7.3% in PEEP, p < .01). In patients with a diffuse loss of aeration, the overinflated lung volumes of thick and thin computed tomography sections were, respectively, 0.6 0.8 mL vs. 16 10 mL in ZEEP (p < .01) and 8 9 mL vs. 73 62 mL in PEEP (p < .05). In patients with a focal loss of aeration, this underestimation was more pronounced: 18 56 mL vs. 127 140 mL in ZEEP (p < .01) and 85 161 mL vs. 322 292 mL in PEEP (p < .01). Conclusions: In patients with acute lung injury, an accurate computed tomography estimation of lung overinflation resulting from positive pressure mechanical ventilation requires high spatial resolution computed tomography sections, particularly when the lung morphology shows a focal loss of aeration. (Crit Care Med 2005; 33:741–749)