Objective: To evaluate the effects of high frequency oscillatory ventilation (HFOV) plus synchronized intermittent mandatory ventilation(SIMV) on treating critical hyaline membrane disease(HMD:grade Ⅲ~Ⅳ). Methods: A total of 53 infants with critical HMD in the NICU of Huaian Maternal and Child Health Hospital from January 2005 to January 2010 were enrolled and divided into two groups: research group (HFOV plus SIMV) and control group(SIMV, or A/C )according the mechanical ventilation mode. X-ray, blood gas analysis, outcome and complications (pneumothorax, intracranial hemorrhage, bronchopulmonary dysplasia) were compared between the two groups. Results: The alteration of X-ray (after 24h treatment), PO2(after 12 h and 24 h treatment) and outcome in research group were better than control group(all P < 0.05). Compared with control group, the incidence of pneumothorax in research group was significantly lower(P < 0.05). But no statistic significance was found in incidence of intracranial hemorrhage and bronchopulmonary dysplasia between two groups(P < 0.05). Conclusion: HFOV plus SIMV can improve lung oxygenation and the outcome, reduce the incidence rate of pneumothorax without increasing the risk of intracranial hemorrhage. In the treatment of critical HMD, HFOV plus SIMV was superior to conventional mandatory ventilation.