Melatonin is a free radical scavenger, a broad-spectrum antioxidant and has well documented immunomodulatory effects. We studied the effects of this hormone on lung damage, oxidative stress and inflammation in a model of ventilator-induced lung injury (VILI), using 8-12 weeks old Swiss mice (n=48). Animals were randomized into three experimental groups: control (not ventilated); low pressure ventilation (Peak inspiratory pressure 15 cmH₂O, PEEP 2 cmH₂O) and high pressure ventilation (Peak inspiratory pressure 25 cmH₂O, PEEP 0 cmH₂O). Each group was divided into two subgroups: 8 animals were treated with melatonin (10mg/Kg intraperitoneally, 30 minutes before the onset of ventilation) and the remaining 8 with vehicle. After two hours of ventilation, lung injury was evaluated by gas exchange, wet-to-dry weight ratio and histological analysis. Levels of malondialdehyde, glutathione peroxidase, interleukins (IL) -1, -6, TNF-, IL-10 and matrix metalloproteinases 2 and 9 in lung tissue were measured as indicators of oxidation status, pro-/antiinflammatory cytokines and matrix turnover respectively. Ventilation with high pressures induced severe lung damage and release of TNF, interleukin-6 and matrix metalloproteinase-9. Treatment with melatonin improved oxygenation and decreased histological lung injury, but significantly increased oxidative stress quantified by malondialdehyde levels. There were no differences in TNF, IL-1, IL-6 or matrix metalloproteinases caused by melatonin treatment, but IL-10 levels were significantly higher in treated animals. These results suggest that melatonin decreases ventilator-induced lung injury by increasing the antiinflamatory response in spite of an unexpected increase in oxidative stress.