Background: The pathophysiology of post-operative cognitive dysfunction remains unclear and there is no widely accepted animal model that can simulate its occurrence. The purpose of this study was to explore the effects of surgical stress on long-term post-operative memory function in mice of different ages. Methods: Healthy C57B1/6J male mice, of either 4- or 16-month-old, were each randomly divided into three subgroups. (1) Control group: neither anesthesia nor surgery was performed; (2) Anesthesia group: general anesthesia was administrated, surgery was not performed; (3) Surgery group: two-thirds partial hepatectomy was completed in about 15 min under general anesthesia. Morris water maze test was performed after 30 days.Results: In mice of both month-ages, the escape latencies as well as the swimming distances decreased significantly across training days (P<0.001). In 4-month-old mice, there were no significant differences among three subgroups. In 16-month-old mice, the escape latency was significantly less in the surgery group than in the control group (P=0.001), and the swimming distance was significantly shorter in the surgery group than in the control and the anesthesia groups (P=0.001 and 0.047, respectively). In the spatial probe test, time spent in the target quadrant was significantly longer in the surgery group than in the combined control and anesthesia group (P=0.037). Conclusions: Partial hepatectomy did not produce significant long-term effects on memory function in 4-month-old mice. However, it significantly improved long-term memory function in 16-month-old mice.