AIM: To investigate the effect of sub-anesthetic dose of esketamine on chronic post-surgery pain (CPSP) in patients undergoing radical mastectomy of breast cancer. METHODS: A total of 120 patients undergoing elective radical mastectomy of breast cancer in the operating room of our hospital from November 2021 to March 2022 were enrolled, aged 35-64 years old, and with American Society of Anesthesiologists (ASA) classification I to II. The subjects were allocated into esketamine group (group E) and sufentanil group (group S), with 60 subjects per group, according to a random number table method. At the beginning of anesthesia induction, patients in group E were given intravenous injection of esketamine 0.3 mg/kg and sufentanil 0.2 μg/kg, and during the maintenance of anesthesia, the administration rate of esketamine was 0.25 mg·kg-1·h-1, sevoflurane was continuously inhaled at 1% to 2%, and stopped 30 minutes before the end of the operation, and a patient-controlled intravenous analgesia (PCIA) pump was connected immediately after the operation, and esketamine 100 mg + sufentanil 100 μg + tropisetron 10 mg were added to the analgesia pump, supplemented with medical 0.9% sodium chloride injection to dilute to 100 mL. At the beginning of anesthesia induction, patients in group O were intravenously injected with sufentanil 0.5 μg/kg, and the administration rate of remifentanil during the anesthesia maintenance period was 0.1-0.3 μg·kg-1·min-1, and stopped 5 minutes before the end of the operation. Sufentanil 150 μg + tropisetron 10 mg was added to the PCIA pump, supplemented with medical 0.9% sodium chloride injection to dilute to 100 mL. The PICA pump parameters in both groups were set to background dose of 2 mL/h, bolus dose was 0.5 mL, and locked time was 15 min. The main outcome was the incidence of CPSP on postoperative 3 months, and the patients were followed up at 3 and 6 months postoperatively to record the occurrence of CPSP. The secondary outcomes were visual analogue scale of pain (VAS), Ramsay sedation scale and the incidence of postoperative adverse events within 48 hours after surgery. Peripheral venous blood was drawn 1 day before operation and 1 day and 3 days after operation, and the concentrations of serum inflammatory factors including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8) were measured. RESULTS: There were 2 lost patients in group S and 3 lost patients in group E. At 3 and 6 months after operation, 27 (46.6%) and 19 (32.8%) patients in group S had CPSP, including 18 (31.0%) and 13 (22.4%) patients with mild pain, respectively. 13 (22.8%) and 8 (14.0%) patients in group E had CPSP, including 8 (14.0%) and 5 (8.8%) patients with mild pain, respectively. The incidence of CPSP in group E was lower than that in group S at 3 and 6 months after operation (P<0.05). The VAS scores and Ramsay sedation scores of the two groups of patients were similar at different time points after operation within 48 h (P>0.05). The analgesic rescue rate within 2 days after operation, the total number of PCIA pump compressions and the number of effective compressions were not similar between the two groups, and there was no statistical significance (P>0.05). Compared with group S, the incidence of nausea and vomiting in group E was significantly lower within 2 days after operation (P<0.05). The serum levels of TNF-α, IL-6 and IL-8 in the group E were significantly decreased on postoperative 1 and 3 d, compared with group S (P<0.05). CONCLUSION: Sub-anesthetic dose of esketamine can inhibit perioperative inflammatory response and lower the incidence of CPSP in patients undergoing breast cancer surgery.