Objective. Meconium aspiration induces acute lung injury (ALI) in neonates born through meconium-stained amniotic fluid. As yet, there is no specific therapy for improving the outcome. Recently, angiotensin-converting enzyme 2 (ACE2), which inactivates angiotensin II (Ang II), has been shown to ameliorate murine ALI. Design. To evaluate the therapeutic potential of this substance, we studied ACE2 in a piglet model of ALI induced by meconium aspiration. Subjects. Twelve anesthetized piglets were subjected in an animal research laboratory. ALI was induced by tracheal meconium instillation. Thereafter, six animals were randomly assigned to the ACE2 group, while another 6 served as control. Measurements. Systemic, pulmonary hemodynamic, and blood gas exchange parameters and Ang II levels were examined before ALI induction and at various time points after administering ACE2 or saline. In addition, ventilation-perfusion distribution of the lung was assessed by the multiple inert gas elimination technique (MIGET). Main Results. Animals treated with ACE2 maintained significantly higher arterial partial pressures of oxygen (Pao2) and lower arterial partial pressures of carbon dioxide (Paco2), respectively. Furthermore, Ang II, which was substantially increased, returned to basal values. Conclusion. In summary, ACE2 improves blood gas exchange in meconium-induced ALI in piglets.