Postoperative cognitive dysfunction (POCD) is one of the main causes of morbidity after noncardiac surgery; however, the pathogenic mechanisms of POCD have remained unclear until now. In this study, we performed apilot study to investigate the association between apolipoproteinE (ApoE) ε4 and POCD in older patients undergoing intravenous anesthesia (IVA) and inhalation anesthesia (IAA). In total, 180patients from Shenzhen People's Hospital were recruited and randomly divided into an IVA group and an IAA group. The IVA group and IAA group received propofol and sevoflurane treatment, respectively. Within 7days after surgery, the mini-mental state examination (MMSE) was used daily to assess the cognitive function of both groups of patients. The genotypes of the ApoE gene were detected using the restriction fragment length polymorphism technique. In addition, the serum levels of (soluble protein-100β)S‑100β and (Interleukin- 6)L‑6 were also analyzed. Compared to the preoperative and IVA groups, the MMSE score in the IAA group significantly decreased at 3days after surgery. Furthermore, the IAA group had ahigher percentageof patients who scored less than 25points than the IVA group at 3days after surgery. The decrease in the MMSE score was closely related to the ApoE ε4 allele in the IAA group, but this correlation was not observed in the IVA group. The levels of S‑100β and IL‑6 were increased sharply in patients with the ε4/ε4 genotype who received IAA compared with IVA at 1day after surgery. The results of the study indicated that the ApoΕ ε4/ε4 genotype was arisk factor for early POCD in older patients undergoing sevoflurane anesthesia.