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Postoperative nausea and vomiting (PONV) is the most common complication after surgery, and opioid administration increases its incidence. We compared the preventive effects of fosaprepitant, a neurokinin-1 (NK1) receptor antagonist, with those of ondansetron on PONV in patients who underwent lower limb surgery with postoperative epidural opioid administration.This prospective, double-blind, randomized study included 38 patients who underwent lower limb surgery. They were randomly allocated to receive intravenous fosaprepitant 150 mg (n = 19; NK1 group) or ondansetron 4 mg (n = 19; ONS group) before general anesthesia. All patients received postoperative epidural fentanyl for pain control. The incidence of nausea and vomiting, complete response rate (no vomiting and no rescue antiemetic use), rescue antiemetic use, nausea score (0-3), and visual analog scale (VAS 0-10) score for pain were recorded at 2, 24, and 48 h after surgery.No patient in the NK1 group experienced vomiting (0%) during the first 24 and 48 h after surgery, while 5 of 19 (26%) patients in the ONS group experienced this complication, indicating a significant difference between groups. There were no significant differences in the incidence of PONV, complete response rate, rescue antiemetic use, nausea score, and VAS score for pain between the NK1 and ONS groups during the study period.Fosaprepitant was more effective than ondansetron in decreasing the incidence of vomiting after lower limb surgery with postoperative opioid administration. Meanwhile, fosaprepitant was not inferior to ondansetron in decreasing the incidence and severity of PONV.