Objective: Air leak syndromes including pneumothorax, pneumomediastinum and pulmonary interstitial emphysema are frequent in neonatal period. Mechanical ventilation with positive pressure is one of the most common causes of these syndromes. The aim of this study was to evaluate predisposing factors and incidence of pneumothorax in newborns under mechanical ventilation., Methods: This descriptive cross sectional study was performed in 400 newborns under mechanical ventilation in intensive care unit of a teaching hospital in Iran from April 2004 to December 2008. Predisposing factors leading to ventilation and incidence of air leak syndromes were studied. Sex, gestational age, birth weight, type of delivery, history of surfactant replacement therapy, ventilator settings and mortality rate were recorded. Statistical analysis was done using SPSS software. Univariate analysis and regression analysis were considered., Findings: Among 400 patients under mechanical ventilation, 102 neonates developed pneumothorax (26%). Fifty six (54.9%) of them were boys and 46 (45.1%) girls. 54.9% of newborns with pneumothorax were preterm and 45.1% term. Birth weight less than 2500g was recorded in 59.8%. Fifty two percent of these neonates were born by cesarean section vs. 32% of newborns without pneumothorax. The most common type (62.7%) of ventilation leading to pneumothorax was Inspiratory Positive Pressure Ventilation (IPPV). Surfactant replacement therapy was recorded in 32.4% of cases with pneumothorax compared to 60.4% of neonates under ventilation without pneumothorax, which was significantly different (P= 0.017)., Conclusion: In newborns surfactant replacement therapy can reduce the risk of pneumothorax caused by mechanical ventilation.