Background: Volume guarantee is a synchronised mode with time-cycled, pressure-limited ventilation, developed to maintain minimal preset mechanical tidal volume. Objective: To compare the effects of synchronised intermittent mandatory ventilation plus volume guarantee (SIMV+VG) with conventional synchronised intermittent mandatory ventilation (SIMV) in preterm neonates with respiratory distress syndrome (RDS). Method: This prospective study included preterm neonates admitted in Neonatal Intensive Care Unit (NICU) from October, 2010 to March, 2011. A total of 28 neonates were randomised in the study with the SIMV and SIMV+VG during initial ventilation and weaning phase. The outcome measures were to compare peak inspiratory pressure (PIP), mean airway pressure (MAP), oxygenation (PaO2/FiO2) and ventilation in both the groups. Result: During the initial ventilation, the oxygenation (based on PaO2/FiO2 ratio) was considerably better in the SIMV+VG (285.6±154) as compared to the SIMV group (156.8±92.9) and it was statistically significant (p=0.025).The compliance in SIMV+VG group was higher than SIMV group but it did not reach statistically significant difference. During the weaning phase, the SIMV+VG group showed hypocarbia (33 mm Hg) whereas the SIMV group showed normocarbia (44 mm Hg); (p=0.025). The compliance was better in the SIMV+VG (2.7 ± 1.8 ml/mbar) as compared to the SIMV (0.7 ± 0.6 ml/mbar). This was statistically significant (p value=0.042). Conclusion: The SIMV+VG is relatively better for weaning from ventilatory support and it enhances the spontaneous respiratory effort.