Objectives <p>To evaluate the safety and efficacy of dexmedetomidine as the primary sedative in neonates.</p> Study design <p>Single center, retrospective study of mechanically ventilated neonates sedated with dexmedetomidine (study group) or opioids/benzodiazepines (control group). Primary outcome was requirement of opioids/benzodiazepines. Secondary outcomes included duration of mechanical ventilation, time to full feeds, bradycardia/hypotension, and unplanned extubation. A subgroup analysis was conducted in premature neonates.</p> Results <p>There were 148 patients (study group <i>n</i> = 91, control group <i>n </i>= 57) included. Patients who received dexmedetomidine had less cumulative exposure to opioids/benzodiazepines. The median opioid/benzodiazepine requirement was 0 mg/kg/day in the study group compared to the control group with 0.36–0.96 mg/kg/day midazolam equivalents and 1.75–4.1 mg/kg/day morphine equivalents. Unplanned extubations were not different between groups indicating similar efficacy. The study group reached full feeds faster than the control group.</p> Conclusion <p>Dexmedetomidine as the primary sedative in neonates is safe and efficacious at minimizing opioids and benzodiazepines in both term and premature neonates.</p> Clinical trial registration <p>N/A</p>