BACKGROUND:: Commonly used sedatives/analgesics can increase the risk of postoperative complications, including delirium. This double-blinded study assessed the neurobehavioral, hemodynamic, and sedative characteristics of dexmedetomidine compared with morphine-based regimen after cardiac surgery at equivalent levels of sedation and analgesia. METHODS:: A total of 306 patients at least 60 yr old were randomized to receive dexmedetomidine (0.1-0.7 μg • kg • h) or morphine (10-70 μg • kg • h) with open-label propofol titrated to a target Motor Activity Assessment Scale of 2-4. Primary outcome was the prevalence of delirium measured daily via Confusion Assessment Method for intensive care. Secondary outcomes included ventilation time, additional sedation/analgesia, and hemodynamic and adverse effects. RESULTS:: Of all sedation assessments, 75.2% of dexmedetomidine and 79.6% (P = 0.516) of morphine treatment were in the target range. Delirium incidence was comparable between dexmedetomidine 13 (8.6%) and morphine 22 (15.0%) (relative risk 0.571, 95% confidence interval [CI] 0.256-1.099, P = 0.088), however, dexmedetomidine-managed patients spent 3 fewer days (2 [1-7] versus 5 [2-12]) in delirium (95% CI 1.09-6.67, P = 0.0317). The incidence of delirium was significantly less in a small subgroup requiring intraaortic balloon pump and treated with dexmedetomidine (3 of 20 [15%] versus 9 of 25 [36%]) (relative risk 0.416, 95% CI 0.152-0.637, P = 0.001). Dexmedetomidine-treated patients were more likely to be extubated earlier (relative risk 1.27, 95% CI 1.01-1.60, P = 0.040, log-rank P = 0.036), experienced less systolic hypotension (23% versus 38.1%, P = 0.006), required less norepinephrine (P < 0.001), but had more bradycardia (16.45% versus 6.12%, P = 0.006) than morphine treatment. CONCLUSION:: Dexmedetomidine reduced the duration but not the incidence of delirium after cardiac surgery with effective analgesia/sedation, less hypotension, less vasopressor requirement, and more bradycardia versus morphine regimen.