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We investigated the effects of ulinastatin on early postoperative cognitive dysfunction (POCD) after one-lung ventilation (OLV) surgery in elderly patients receiving neoadjuvant chemotherapy. Eighty elderly patients with preoperative neoadjuvant chemotherapy scheduling for radical esophagectomy under OLV were recruited. They were randomly divided into an ulinastatin pretreatment group (U group, n = 40) and a control group (C group, n = 40). The U group received 10,000 U/kg ulinastatin before anesthesia and 5000 U/kg daily on postoperative days 1 to 3, while C group received saline. Levels of interleukin (IL)-6, IL-10, C-reactive protein (CRP), and S-100β protein were assayed before surgery, at the end of surgery, and on postoperative days 1 and 3. Patients underwent cognitive assessment 1 day before and 7 days after surgery. 38 patients in U group and 37 patients in C group completed the neuropsychological tests. The U group had a lower incidence of POCD than C group (23.7 % versus 45.9 %, P = 0.043). The levels of S-100β protein, IL-6, IL-10, and CRP in both groups increased after surgery. The postoperative concentrations of S-100β protein, IL-6, and CRP in U group were lower than those in C group. On postoperative day 3, compared with C group, the level of CRP in U group was lower, while that of IL-10 was higher. These findings demonstrate that ulinastatin can attenuate the elevation of S100β protein levels and the incidence of POCD, most likely by the mechanism of reducing serum IL-6 and CRP levels and increasing IL-10 levels. [ABSTRACT FROM AUTHOR]