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To compare safety and clinical outcomes of prolonged infusions with standard-dose (≤0.7 μg/kg/h) dexmedetomidine (SDD) or high-dose (>0.7 μg/kg/h) dexmedetomidine (HDD) to propofol in critically ill trauma patients.This was a retrospective review of 127 adult mechanically ventilated trauma patients between 2008 and 2009, who received propofol, SDD, or HDD for >24 hours. Primary outcomes were significant changes in blood pressure or heart rate. Secondary outcomes included hospital and intensive care unit (ICU) length of stay (LOS), ventilator time, and any concomitant analgesic, sedative, and antipsychotic use. Pairwise comparisons were based on Wilcoxon rank-sum test for continuous data and Pearson's chi-square test for categorical data. Statistical significance was defined as p value <0.05.Patients in HDD group had higher rate of hypotension (98% vs. 78%; p = 0.02) but no significant differences in heart rate compared with propofol group. These patients had median longer hospital LOS (25 days vs. 12 days; p < 0.001), ICU LOS (20 days vs. 12 days; p = 0.004), and longer ventilator time (14 days vs. 7 days; p = 0.008). They also had increased requirements for oxycodone (74% vs. 40%; p = 0.003), midazolam (36% vs. 8%; p = 0.004), and haloperidol (50% vs. 24%; p = 0.02). Patients in SDD group had longer hospital LOS compared with propofol group (21 days vs. 13 days; p < 0.001).Higher doses of dexmedetomidine may result in higher incidence of hypotension, longer LOS, and increased concomitant analgesic, sedative, and antipsychotic use, requiring further evaluation in trauma patients.