BACKGROUND: Volume-controlled ventilation modes have been shown to reduce duration of mechanical ventilation, incidence of chronic lung disease, failure of primary mode of ventilation, hypocarbia, severe intraventricular hemorrhage, pneumothorax, and periventricular leukomalacia in preterm infants when compared with pressure limited ventilation modes. Volume-guarantee (VG) ventilation is the most commonly used mode for volume-controlled ventilation. Assist control, pressure-support ventilation (PSV), and synchronized intermittent mandatory ventilation (SIMV) can be combined with VG; however, there is a lack of knowledge on the superiority of each regarding clinical outcomes. Therefore, we investigated the effects of SIMV +VG and PSV+ VG on ventilatory parameters, pulmonary inflammation, morbidity, and mortality in preterm infants. METHODS: Preterm infants who were born in our hospital between 24-32 weeks gestation and needed mechanical ventilation for respiratory distress syndrome were considered eligible. Patients requiring high-frequency oscillatory ventilation for primary treatment were excluded. Subjects were randomized to either SIMV + VG or PSV + VG. Continuously recorded ventilatory parameters, clinical data, blood gas values, and tracheal aspirate cytokine levels were analyzed. RESULTS: The study enrolled 42 subjects. Clinical data were similar between groups. PSV +VG delivered closer tidal volumes to set tidal volumes (60% vs 49%, P = .02). Clinical data, including days on ventilation, morbidity, and mortality, were similar between groups. Chronic lung disease occurred less often and heart rate was lower in subjects who were ventilated with PSV + VG. The incidence of hypocarbia and hypercarbia were similar. Interleukin-1 beta in the tracheal aspirates increased during both modes. CONCLUSION: PSV + VG provided closer tidal volumes to the set value in ventilated preterm infants with respiratory distress syndrome and was not associated with overventilation or a difference in mortality or morbidity when compared to SIMV + VG. Therefore, PSV + VG is a safe mode of mechanical ventilation to be used for respiratory distress syndrome.