OBJECTIVES: Delirium is the most common postoperative neurological complication and some evidence suggests that dexmedetomidine is associated with a decreased incidence of delirium. This study is designed to assess the effect of dexmedetomidine on postoperative delirium (POD) in elderly patients with mild cognitive impairment (MCI). METHODS: Sixty geriatric patients with MCI were enrolled and ramdomly divided into two groups by a computer-generated randomisation sequence: dexmedetomidine group (D group) and normal saline group (C group). Patients in D group received a loading dose of 0.5 μg/kg dexmedetomidine over 10 minutes before anesthesia induction, followed by a continuous infusion of 0.4 μg·kg(-1)·h(-1) until 30 minutes before the end of surgery; equal volume of normal saline was given in C group. Blood samples were extracted to detect the concentration of cytokines, including tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), heme oxygenase-1 (HO-1), matrix metalloproteinase-9 (MMP-9), and glial fibrillary acidic protein (GFAP) before anesthesia induction (T(1)), before suture (T(2)), and 30 minutes after surgery (T(3)). Postoperative recovery times were recorded. Delirium was assessed with the 3-Minute Diagnostic Interview for confusion assessment method during the first 7 days postoperatively. RESULTS: POD occurred in 10 (33.3%) of 30 patients in C group, and in 3 (10%) of 30 patients given dexmedetomidine (odds ratio [OR] 0.222, 95% CI 0.054-0.914; P = 0.028). The serum concentrations of TNF-α, MMP-9, and GFAP were significantly increased and IL-10 was decreased in the C group than in the D group at T(2) and T(3). No differences were observed between groups in the level of HO-1. Analysis using random-effect multivariable logistic regression indicated that POD was associated with GFAP (odds ratio [OR] 16.691, 95% CI 2.288-121.746; P = 0.005). The positive predictive ability of the multivariate logistic regression model tested by ROC analysis showed an area under the curve of 0.713 (95% CI, 0.584-0.842). CONCLUSIONS: Dexmedetomidine can alleviate POD in elderly patients with MCI and may be related to reduce the neuroinflammation by lowering the permeability of blood-brain barrier.