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Hypoproteinemia, fluid retention, and weight gain are associated with development of acute lung injury and mortality in critically ill patients, without proof of cause and effect. We designed a clinical trial to determine whether diuresis and colloid replacement in hypoproteinemic patients with acute lung injury would improve pulmonary physiology.Prospective, randomized, double-blind, placebo-controlled trial.All adult intensive care units from two university hospitals.Thirty-seven mechanically-ventilated patients with acute lung injury and serum total protein ≤5.0 g/dL.Five-day protocolized regimen of 25 g of human serum albumin every 8 hrs with continuous infusion furosemide, or dual placebo, targeted to diuresis, weight loss, and serum total protein.Measured outcomes included change in weight, serum total protein, fluid balance, hemodynamics, respiratory system compliance, and oxygenation. Baseline characteristics were similar between groups (treatment, n = 19; control, n = 18), with trauma being the major cause of acute lung injury. Diuresis and weight loss over 5 days (5.3 kg more in the treatment group, p = .04) was accompanied by improvements in the Pao2/Fio2 ratio in the treatment group within 24 hrs (from 171 to 236, p = .02). Respiratory mechanics were unchanged. Mean arterial pressure increased from 80 to 88 mm Hg (p = .10), and heart rate decreased from 110 to 95 beats/min (p = .008) over time in the treatment group. No difference in mortality was observed, with favorable trends in measures of intensive care.Albumin and furosemide therapy improves fluid balance, oxygenation, and hemodynamics in hypoproteinemic patients with acute lung injury. Determining the effect of this simple therapy on cost, outcomes, and other patient populations requires further study.