Rationale: The pathophysiological relationship between fluid administration, fluid balance, and mechanical ventilation in the development of lung injury is unclear. Objectives: To quantify the relative contribution of mechanical power and fluid balance in the development of lung injury. Methods: Thirty-nine healthy female pigs, divided into four groups, were ventilated for 48 hours with high (~18J/min) or low (~6J/min) mechanical power; and high (~4L) or low (~1L) targeted fluid balance. Measurements and Main Results: We measured physiological variables e.g., end-expiratory lung gas volume, respiratory-system mechanics, gas-exchange and hemodynamics, and pathological variables, i.e., lung weight, wet-to-dry ratio, and histology score of lung injury. End-expiratory lung gas volume, respiratory system elastance, strain and oxygenation significantly worsened in the two groups assigned to receive high fluid balance, irrespective of the mechanical power received. All four groups had similar lung weight (i.e., lung edema), lung wet-to-dry ratio and pathological variables. Animals with higher fluid balance developed more ascites, which was associated with a decrease in end-expiratory lung gas volume. Conclusions: In conclusion, our study did not detect a significant difference in lung injury between high and low mechanical power. Some damage is directly attributable to mechanical power, while additional injury appears to result indirectly from high fluid balance, which reduces end-expiratory lung gas volume, with ascites playing an important role in this process.