OBJECTIVE: To explore the immunomodulatory mechanism and optimal dose of dexmedetomidine (DEX) for preventing postoperative cognitive dysfunction (POCD) in elderly patients undergoing spinal surgery. OBJECTIVE: A total of 120 elderly patients undergoing elective spinal surgery with general anesthesia were randomized into 4 groups to receive a loading dose of 0.3 μg/kg DEX for 10 min before anesthesia induction followed by maintenance doses of 0.2, 0.5, and 0.8 μg · kg·h (low-, medium-, and high-dose DEX groups, respectively) or an equal volume of normal saline (control group). DEX and saline was discontinued 40 min before the end of the surgery. Before induction (D) and on day 1 (D), day 3 (D) and day 7 (D) after the operation, the cognitive function of the patients was assessed using the MMSE scale and their serum levels of β-amyloid (Aβ), TNF-α, IL-1β and IL-6 were measured. The occurrence of adverse effects including bradycardia and hypotension and the recovery time of the patients were recorded. OBJECTIVE: Compared with those on D, serum levels of Aβ, IL-1β, IL-6, and TNF-α on D were markedly increased in all the groups ( < 0.05); the levels of Aβ decreased to the baseline level on D in medium- and high-dose DEX groups ( > 0.05) but remained high in the other two groups. On D, TNF-α, L-1β and IL-6 recovered their baseline levels in medium- and high-dose DEX groups ( > 0.05) but remained elevated in the other two groups. The incidences of POCD in medium- and high-dose DEX groups were comparable but significantly lower than that in the control group ( < 0.05). The incidences of hypotension and bradycardia were the highest in high-dose DEX group ( < 0.01), which also had longer recovery time than the other 3 groups ( < 0.05). OBJECTIVE: With a loading dose of 0.3 μg/kg followed by a maintenance doses of 0.5 μg · kg·h, DEX can effectively reduce the incidence of POCD in elderly patients undergoing spinal surgery by inhibiting the production of Aβ and pro-inflammatory cytokines.