Objective: To study the effect of proportional assist ventilation (PAV) on physiology and respiratory mechanics in very low birth weight (VLBW) infants with ventilator dependence by comparison with conventional assist/control (A/C) ventilation. Methods: Forty-six infants with ventilator dependence were randomly divided into two groups according to the ventilation model: PAV (n = 23) and A/C (n = 23). The gain of resistive and elastic unloading was set based on the runway method in the PAV group. Ventilation parameters were set based on the conventional method in the A/C group. Infants were observed for 30 minutes three times per day for three consecutive days. Arterial gas analysis results, transcutaneous saturation of oxygen (SPO 2), heart rate, blood pressure (BP), respiratory rate (RR), mean airway pressure (MAP), peak inspiratory pressure (PIP), tide volume (VT), minute volume (MV) and oxygenation index(OI), were compared between the two groups. Results: Compared with the A/C group, PaO 2 and OI in the PAV group were significantly higher while PIP and MAP were significantly lower. There were no significant differences in FiO 2, SPO 2, pH, PaCO 2, PEEP, VT, MV and RR between the two groups. Although mean arterial blood pressure and heart rate in the PAV group were not different from the A/C group, beat-to-beat variabilities in systolic and diastolic arterial blood pressure were significantly lower in the PAV group than in the A/C group. Conclusions: PAV may safely maintain gas exchange at lower airway pressures compared with A/C ventilation in VLBW infants. It can also improve oxygenation and infant-ventilator synchronization.