The incidence of postoperative nausea and vomiting (PONV) is 30-50% after surgery. PONV occurs frequently, especially after craniotomy. In this study, we investigated the preventive effects on PONV in a randomized study by comparing patients who had been administered fosaprepitant, a neurokinin-1 (NK1) receptor antagonist, or ondansetron intravenously. Sixty-four patients undergoing craniotomy were randomly allocated to receive fosaprepitant 150 mg i.v. (NK1 group, n = 32) or ondansetron 4 mg i.v. (ONS group, n = 32) before anesthesia. The incidence of vomiting was significantly less in the NK1 group, where 2 of 32 (6%) patients experienced vomiting compared to 16 of 32 (50%) patients in the ONS group during the first 24 and 48 hours following surgery. Additionally, the incidence of complete response (no vomiting and no rescue antiemetic use) was significantly higher in the NK1 group than in the ONS group, and was 66% versus 41%, respectively, during the first 24 hours, and 63% versus 38%, respectively, during the first 48 hours. In patients undergoing craniotomy, fosaprepitant is more effective than ondansetron in increasing the rate of complete response and decreasing the incidence of vomiting at 24 and 48 hours postoperatively.