AbstractExcessive tidal volume (VT) can lead to lung injury, hypocarbia, and neurologic damage. Volume guarantee (VG) uses exhaled VT as the control variable to reduce the risk of volutrauma and more closely control PaCO2. Our objective was to test the hypothesis that VG combined with assist/control (A/C) will maintain PaCO2 and VT within target range more consistently than assist/control alone during the first 72 hr of life in ventilated preterm infants. Eligible infants were randomly assigned to A/C + VG or A/C alone. Data were recorded directly from the pressure and volume module of the Draeger Babylog 8000+ ventilator. Arterial blood gases were obtained every 2–6 hr, as clinically indicated. In A/C, inspiratory pressure was adjusted to achieve a VT of 4–6 ml/kg. In VG, the target VT was 5 ml/kg. Subsequent adjustments were made by the clinical team in response to arterial blood gas measurements (ABG). Proportion of breaths and PaCO2 values outside the target range were compared by χ2, and continuous variables by t‐test. There were no differences in demographic or baseline ventilator variables between the 18 infants in the two groups. For 1,805/11,950 breaths (15.1%), VT was > target with A/C + VG, vs. 2,503/9,853 (25.4%) with A/C (P < 0.001). VT was < target for 21.7% of breaths with A/C + VG, vs. 35.7% with A/C (P < 0.001). Twenty percent of PaCO2 values were < target, with A/C + VG vs. 36.3% with A/C, P < 0.05. The proportion of PaCO2 values > target was similar in the two groups. Oxygenation and mean pH were not different. No complications related to mechanical ventilation were observed. In conclusion, VG significantly reduced hypocarbia and excessively large VT. This suggests the potential to reduce pulmonary and neurologic complications of mechanical ventilation. Larger studies are needed to establish safety and demonstrate such benefits. © 2004 Wiley‐Liss, Inc.