Rationale: Noisy ventilation with variable VT may improve respiratory function in acute lung injury. Objectives: To determine the impact of noisy ventilation on respiratory functionand its biological effects on lung parenchyma compared with conventional protective mechanical ventilation strategies. Methods: In a porcine surfactant depletion model of lung injury, we randomly combined noisy ventilation with the ARDS Network protocol or the open lung approach (n 5 9 per group). Measurements and Main Results: Respiratory mechanics, gas exchange, and distribution of pulmonary blood flow were measured at intervals over a 6-hour period. Postmortem, lung tissue was analyzed to determine histological damage, mechanical stress, and inflammation. We found that,at comparable minute ventilation, noisy ventilation(1) improved arterial oxygenation and reduced mean inspiratory peak airway pressure and elastance of the respiratory system compared with the ARDS Network protocol and the open lung approach, (2) redistributed pulmonary blood flow to caudal zones compared with the ARDS Network protocol and to peripheral ones compared with the open lung approach, (3) reduced histological damage in comparison to both protective ventilation strategies, and (4) did not increase lung inflammation or mechanical stress. Conclusions: Noisy ventilation with variable VT and fixed respiratory frequency improves respiratory function and reduces histological damage compared with standard protective ventilation strategies.