BACKGROUND: A strategy of mechanical ventilation that limits airway pressure and tidal volume while permitting hypercapnia has been recommended for patients with the acute respiratory distress syndrome. The goal is to reduce lung injury due to overdistention. However, the efficacy of this approach has not been established. METHODS: Within 24 hours of intubation, patients at high risk for the acute respiratory distress syndrome were randomly assigned to either pressure- and volume-limited ventilation (limited-ventilation group), with the peak inspiratory pressure maintained at 30 cm of water or less and the tidal volume at 8 ml per kilogram of body weight or less, or to conventional ventilation (control group), with the peak inspiratory pressure allowed to rise as high as 50 cm of water and the tidal volume at 10 to 15 ml per kilogram. All other ventilatory variables were similar in the two groups. RESULTS: A total of 120 patients with similar clinical features underwent randomization (60 in each group). The patients in the limited-ventilation and control groups were exposed to different mean (+/-SD) tidal volumes (7.2+/-0.8 vs. 10.8+/-1.0 ml per kilogram, respectively; P<0.001) and peak inspiratory pressures (23.6+/-5.8 vs. 34.0+/-11.0 cm of water, P<0.001). Mortality was 50 percent in the limited-ventilation group and 47 percent in the control group (relative risk, 1.07; 95 percent confidence interval, 0.72 to 1.57; P=0.72). In the limited-ventilation group, permissive hypercapnia (arterial carbon dioxide tension, >50 mm Hg) was more common (52 percent vs. 28 percent, P=0.009), more marked (54.4+/-18.8 vs. 45.7+/-9.8 mm Hg, P=0.002), and more prolonged (146+/-265 vs. 25+/-22 hours, P=0.017) than in the control group. The incidence of barotrauma, the highest multiple-organ-dysfunction score, and the number of episodes of organ failure were similar in the two groups; however, the numbers of patients who required paralytic agents (23 vs. 13, P=0.05) and dialysis for renal failure (13 vs. 5, P= 0.04) were greater in the limited-ventilation group than in the control group. CONCLUSIONS: In patients at high risk for the acute respiratory distress syndrome, a strategy of mechanical ventilation that limits peak inspiratory pressure and tidal volume does not appear to reduce mortality and may increase morbidity.