Management of pain and sedation therapy is a vital component of optimizing patient outcomes; however, the ideal pharmacotherapy regimen has not been identified in the postoperative cardiac surgery population. We sought to evaluate efficacy and safety outcomes between postoperative mechanically ventilated cardiac surgery patients receiving dexmedetomidine versus propofol therapy upon arrival to the intensive care unit (ICU). We conducted a single center, descriptive study of clinical practice at a 20-bed cardiac surgery ICU in a tertiary academic medical center. Adult mechanically ventilated postcardiac surgery patients who received either dexmedetomidine or propofol for sedation therapy upon admission to the ICU between October 20, 2006 and December 15, 2006 were evaluated. A pharmacy database was used to identify patients receiving dexmedetomidine or propofol therapy for perioperative sedation during cardiac surgery. Patients were matched according to surgical procedure type. Fifty-six patients who received either dexmedetomidine (n = 28) or propofol (n = 28) were included in the analysis. No differences in the ICU length of stay (58.67 ± 32.61 vs. 61 ± 33.1 hours; P = 0.79) and duration of mechanical ventilation (16.21 ± 6.05 vs. 13.97 ± 4.62 hours; P = 0.13) were seen between the propofol and dexmedetomidine groups, respectively. Hypotension (17 [61%] vs. 9 [32%]; P = 0.04), morphine use (11 [39.3%] vs. 1 [3.6%]; P = 0.002), and nonsteroidal anti-inflammatory use (7 [25%] vs. 1 [3.6%]; P = 0.05) occurred more during dexmedetomidine therapy versus propofol. Dexmedetomidine therapy resulted in a higher incidence of hypotension and analgesic consumption compared with propofol-based sedation therapy. Further evaluation is needed to assess differences in clinical outcomes of propofol and dexmedetomidine-based therapy in mechanically ventilated cardiac surgery patients.