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Background: Postoperative nausea and vomiting (PONV) are adverse effects after surgery, which may increase the risk of complications. Aprepitant is a neurokinin‐1 receptor blocker and has been shown to reduce chemotherapy‐related nausea and vomiting and PONV. However, its role in endoscopic skull base surgery remains unclear. The purpose of this study was to evaluate the effect of aprepitant in reducing PONV in endoscopic transsphenoidal (TSA) pituitary surgery. Methods: A retrospective chart review between July 2021 and January 2023 of 127 consecutive patients who underwent TSA was performed at a tertiary academic institution. Patients were divided into 2 groups based on preoperative aprepitant use. Two groups were matched based on known risk factors of PONV (age, sex, nonsmoking, and history of PONV). The primary outcome was the incidence of PONV. Secondary outcome measures included the number of anti‐emetic use, length of stay, and postoperative cererebrospinal fluid (CSF) leak. Results: After matching, 48 patients were included in each group. The aprepitant group demonstrated a significantly lower incidence of vomiting than the non‐aprepitant group (2.1% vs 22.9%, p = 0.002). The number of nausea episodes and anti‐emetic use decreased with aprepitant use (p < 0.05). There was no difference in the incidence of nausea, length of stay, or postoperative CSF leak. Multivariate analysis demonstrated that aprepitant decreased the incidence of postoperative vomiting with odds ratio of 0.107. Conclusion: Aprepitant may serve as a useful preoperative treatment to reduce PONV in patients undergoing TSA. Further studies are needed to evaluate its impact in other arenas of endoscopic skull base surgery. [ABSTRACT FROM AUTHOR]