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Background and Aims: Post-discharge nausea and vomiting (PDNV) is a pertinent problem in patients undergoing ambulatory surgery. The objective of this study was to assess the efficacy of the novel drug olanzapine, which has proved its efficiency in patients undergoing highly emetogenic chemotherapy for PDNV prevention. Methods: This randomised controlled trial recruited 106 adult patients (18-65 years) undergoing highly emetogenic daycare surgeries with propofol-based general anaesthesia (GA). Group O received preoperative oral olanzapine 10 mg, and Group C, acting as a control, received 8 mg of intravenous dexamethasone and 4 mg of ondansetron intraoperatively. The primary outcome was nausea (numeric rating scale >3) and/or vomiting 24 h after discharge. Secondary outcomes included nausea and vomiting in the post-anaesthesia care unit (PACU), severe nausea, vomiting and side effects. Normality was assessed using the Shapiro-Wilk test, and the independent samples t-test or the Mann-Whitney U test was used to compare continuous variables. Fisher's exact test was used to assess any non-random associations between the categorical variables. Results: The incidence and severity of postoperative nausea and vomiting were similar in both groups within PACU (four patients experienced nausea and vomiting, three had severe symptoms in Group O, P = 0.057) and in the post-discharge period (three patients in Group O had nausea and vomiting compared to five patients in Group C, of which four were severe, P = 0.484). The side effects (sedation, dizziness, and light-headedness) were comparable between the two groups. Conclusion: A single preoperative oral olanzapine can be an effective alternative to standard antiemetic prophylaxis involving dexamethasone and ondansetron for preventing PDNV in highly emetogenic daycare surgeries with propofol-based GA. Keywords: Ambulatory surgery, dexamethasone, emetogenic, general anaesthesia, olanzapine, ondansetron, postoperative nausea and vomiting, propofol, Author(s): Binayak Deb [1]; Kulbhushan Saini (corresponding author) [1]; Suman Arora [1]; Sanjay Kumar [1]; Shiv L. Soni [1]; Manu Saini [2] INTRODUCTION Post-discharge nausea and vomiting (PDNV) refers to [...]