Objective: To investigate the differences in the effects of assist/control ventilation, A/C ventilation and high frequency ventilation (HFOV) in the treatment of neonatal respiratory failure. Methods: A total of 88 neonates with respiratory failure were randomly divided into A/C group and HFOV group, 44 cases in each group. Record and compare the blood gas of the two groups before treatment and 24 h and 48 h after treatment. The clinical efficacy and complications of the two groups were compared. Results: Two groups treated 24 h, 48 h after arterial partial pressure of carbon dioxide PaCO2, oxygenation index (OI), respiratory index (RI) is lower than before treatment, partial pressure of oxygen, arterial oxygen partial pressure PaO2, arterial carbon dioxide partial pressure/oxygen concentration (PaO2/FiO2) elevated, difference was statistically significant (P<0.05). HFOV group had better blood gas analysis than A/C group after 24 h, 48h treatment, difference was statistically significant (P<0.05). The total clinical efficiency of HFOV group was 91.318% higher than that of A/C group 77.27%, 15.91% of total complications were lower than 34.09% in A/C group, difference was statistically significant (P<0.05). Conclusion: A/C and HFOV invasive ventilation can effectively improve the blood gas analysis index of neonatal respiratory failure, but HFOV mode has better clinical effect and lower complication rate.