Inhaled nitric oxide has been shown to improve oxygenation in acute lung injury. To evaluate the clinical efficacy of low-dose (5-ppm) inhaled nitric oxide in patients with acute lung injury. Multicenter, randomized, placebo-controlled study, with blinding of patients, caregivers, data collectors, assessors of outcomes, and data analysts (triple blind), conducted in the intensive care units of 46 hospitals in the United States. Patients were enrolled between March 1996 and September 1999. Patients (n = 385) with moderately severe acute lung injury, a modification of the American-European Consensus Conference definition of acute respiratory distress syndrome (ARDS) using a ratio of PaO2 to FiO2 of < or =250, were enrolled if the onset was within 72 hours of randomization, sepsis was not the cause of the lung injury, and the patient had no significant nonpulmonary organ system dysfunction at randomization. Patients were randomly assigned to placebo (nitrogen gas) or inhaled nitric oxide at 5 ppm until 28 days, discontinuation of assisted breathing, or death. The primary end point was days alive and off assisted breathing. Secondary outcomes included mortality, days alive and meeting oxygenation criteria for extubation, and days patients were alive following a successful unassisted ventilation test. An intent-to-treat analysis revealed that inhaled nitric oxide at 5 ppm did not increase the number of days patients were alive and off assisted breathing (mean SD, 10.6 9.8 days in the placebo group and 10.7 9.7 days in the inhaled nitric oxide group; P =.97; difference, -0.1 day 95% confidence interval, -2.0 to 1.9 days). This lack of effect on clinical outcomes was seen despite a statistically significant increase in PaO2 that resolved by 48 hours. Mortality was similar between groups (20% placebo vs 23% nitric oxide; P =.54). Days patients were alive following a successful 2-hour unassisted ventilation trial were a mean (SD) of 11.9 (9.9) for placebo and 11.4 (9.8) for nitric oxide patients (P =.54). Days alive and meeting criteria for extubation were also similar: 17.0 placebo vs 16.7 nitric oxide (P =.89). Inhaled nitric oxide at a dose of 5 ppm in patients with acute lung injury not due to sepsis and without evidence of nonpulmonary organ system dysfunction results in short-term oxygenation improvements but has no substantial impact on the duration of ventilatory support or mortality.