BACKGROUND AND AIMS: Postoperative delirium (POD) is a common and serious surgical complication among the elderly, especially in those with amnestic mild cognitive impairment (aMCI). Dexmedetomidine (DEX) is neuroprotective for delirium. In this study, we determined the effect of intravenously administered DEX during general anesthesia on POD in elderly aMCI patients undergoing elective hip joint or knee joint or shoulder joint replacement surgery. METHODS: This was a prospective, randomized parallel-group study of aMCI (n = 80) and normal elderly patients (n = 120). Prior to surgery, all subjects underwent neuropsychological assessment and were assigned to one of four groups: the aMCI DEX group (MD group, n = 40), the aMCI normal saline group (MN group, n = 40), the control DEX group (CD group, n = 60), and the control normal saline group (CN group, n = 60). The confusion assessment method was used to screen POD on postoperative days 1, 3, and 7. RESULTS: We found patients age was positively correlated with POD incidence in the MN group (p < 0.05) but not in the CN group (p < 0.05). DEX treatment significantly decreased POD incidence in both control and aMCI groups relative to their respective placebo groups (all p < 0.05). The fraction of patients whose normal cognitive function was not restored by day 7 after surgery was significantly higher in the MN group than the MD and CN groups (all p < 0.05). CONCLUSIONS: These findings suggested that DEX treatment during surgery significantly reduced POD incidence in both normal and aMCI elderly patients, suggesting that it may be an effective option for the prevention of POD.