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STUDY OBJECTIVE There were few clinical data dosing and timing regimen for preventing postoperative delirium. The present study aimed to investigate the effect of the timing and dose of dexmedetomidine on postoperative delirium in elderly patients after laparoscopic major non-cardiac surgery. PATIENTS AND INTERVENTIONS A total of 354 patients >65 years of age undergoing laparoscopic major non-cardiac surgery under general anesthesia received a dexmedetomidine 1 μg/kg bolus followed by 0.2-0.7 μg/kg/h infusion from induction of anesthesia to the end of surgery [group D1]); a dexmedetomidine (1 μg/kg bolus [group D2]); or saline (group S) 15 min before the end of surgery. MEASUREMENTS The incidence and duration of delirium for 5 days after surgery and the cytokine (tumor necrosis factor-alpha TNFα, interleukin [IL]-1 β, IL-2, IL-6, IL-8, and IL-10) and cortisol levels were measured 1 h and 24 h after surgery. MAIN RESULTS Group D1 reduced incidence and duration of delirium and group D2 decreased its duration in patients with delirium compared to group S. IL-6 levels were significantly lower at 1 h and 24 h after surgery in group D1 than in group S, and lower at 24 h after surgery than in group D2. IL-6 levels in group D2 were significantly lower only at 1 h after surgery than in group S. However, IL-6 levels in delirious patients in group D2 were significantly lower at 1 h and 24 h after surgery than those in group S. Cortisol levels 1 h after surgery were significantly lower in groups D1 and D2 than in group S. CONCLUSIONS The dose and timing of dexmedetomidine appeared to be important in preventing delirium. The reduced incidence and duration of delirium by dexmedetomidine was associated with reduced levels of IL-6 24 h after surgery.