Dexmedetomidine (DEX) is an α-adrenergic agonist that has been used for sedation during invasive procedures and endotracheal intubation. In pediatric burn injury, DEX has been shown to be safe as a long-term sedative in the intensive care unit (ICU). However, comparison of DEX with traditional sedatives, such as midazolam, for sedation in pediatric burn injury has not been performed. The purpose of this study was to compare DEX with midazolam in terms of sedation, efficacy, and side effects in children with burn injury. A retrospective review of all children with a TBSA burn injury ≥20% admitted from December 2008 to September 2010 was performed. Children who received a continuous DEX infusion were compared with children receiving a continuous midazolam infusion. Data collected included: age, TBSA burn, ventilator days, ICU days, hypotensive episodes, bradycardic episodes, and Richmond Agitation Score (RAS). A total of 21 patients who received DEX infusions were compared with 21 age-matched and burn size–matched patients who received midazolam infusions. Of the 21 DEX patients, nine also received midazolam infusions, eight prior to DEX and one after. These patients did not receive DEX and midazolam simultaneously. There was no difference in age (6.9 vs 6.4 years), TBSA (45.5 vs 49.2%), ICU days (45.3 vs 55.4), and ventilator days (38.5 vs 45.5) between the DEX and midazolam patients, respectively. The mean duration of infusion was 22.5 ± 24.9 days for DEX and 20.1 ± 24.8 days for midazolam. DEX patients had a mean RAS of −0.91 ± 0.8. Midazolam patients were more sedated with a mean RAS of −1.33 ± 0.7. Only one episode of bradycardia was noted in the DEX group. The DEX group had fewer hypotensive episodes (mean arterial pressure <60 mm Hg) while on infusion compared with the midazolam group (15.8 vs 29.7 episodes). Thus, it can be surmised that DEX is a safe and effective sedative for pediatric burn patients. Compared to midazolam, DEX may provide more effective sedation and less sedation-related hypotension.