Objective: We aimed to investigate the effect of neo-adjuvant chemotherapy on postoperative cognitive dysfunction (POCD) in elderly patients who underwent one-lung ventilation (OLV) surgery. Methods: A total of 90 esophageal carcinoma patients aged 60 years old or older were included. These patients were scheduled for esophagectomy, including two or three-field lymphadenectomy, and were randomly divided into two groups based on the American Society of Anesthesiologists status (I or II) and the Tumor-Node-Metastasis (TNM) classification stage (II orIII), as follows: the neo-adjuvant chemotherapy group (Group N: n=45) that received preoperative neo-adjuvant chemotherapy; and the control group (Group C: n=45) that did not receive chemotherapy. The neuropsychological test was performed 1 d before and 7 d after surgery to evaluate the changes in cognitive function. The incidence of POCD was also determined via the Z-value method in the two groups. Results: A total of 44 patients in Group N and 41 patients in Group C completed the neuropsychological tests. No statistical differences were observed in the demographics, TNM stage, and the intraand post-operative clinical data between the groups. POCD was observed in 21 of the patients in Group N (47.7%) and 11 of the patients in Group C (26.8%), and the differences were significant (χ=3.949, P=0.047). Conclusion: Neo-adjuvant chemotherapy can aggravate the impairment of cognitive function in the elderly patients undergoing OLV surgery and can significantly increase the incidence of POCD.