OBJECTIVE Volume guarantee (synchronized intermittent mandatory ventilation [SIMV]+VG) is a novel mode of SIMV for automatic adjustment of the peak inspiratory pressure to ensure a minimum set mechanical tidal volume (V(T mech)). The objective of this study was to compare the effects of SIMV+VG with conventional SIMV on ventilation and gas exchange in a group of very low birth weight infants recovering from acute respiratory failure. METHODS Nine infants were initially studied during 2 consecutive 60-minute ventilatory modalities of conventional SIMV (ventilator settings by clinical team) and SIMV+VG 4.5 (V(T mech) set at 4.5 mL/kg) in random order. Eight additional infants were studied during the same ventilatory modalities plus 1 additional epoch consisting of SIMV+VG 3.0 (V(T mech) set at 3.0 mL/kg). RESULTS Peak inspiratory pressure was significantly lower during SIMV+VG 3.0. Mean airway pressure, V(T mech), number of large V(T mech) (>7 mL/kg), and mechanical minute ventilation (V'(E)) were reduced during SIMV+VG 4.5 compared with SIMV and were further reduced during SIMV+VG 3.0. Spontaneous V'(E) increased during SIMV+VG 4.5 and was even higher during SIMV+VG 3.0. The resulting total V'(E) was higher during both SIMV+VG modes compared with SIMV. Arterial oxygen saturation by pulse oximetry, transcutaneous carbon dioxide tension, and fraction of inspired oxygen did not differ significantly, although transcutaneous carbon dioxide tension increased slightly during SIMV+VG 3.0. CONCLUSIONS The short-term use of SIMV+VG resulted in automatic weaning of the mechanical support and enhancement of the spontaneous respiratory effort while maintaining gas exchange relatively unchanged in comparison to conventional SIMV.