Background: Postoperative nausea and vomiting still represents a major problem after surgery. Although risk factors for postoperative nausea and vomiting and procedures to reduce postoperative nausea and vomiting have been described, the incidence of postoperative nausea and vomiting remains high. The aim of the present study was to investigate the potential role of the proton pump inhibitor esomeprazole to reduce postoperative nausea and vomiting after elective surgery. Methods: In a randomized, double-blind trial, ASA I–III patients at high risk for postoperative nausea and vomiting received esomeprazole tablets 3 × 40 mg or matching placebo the evening before surgery, 2 h preoperatively and 24 h postoperatively. Total intravenous anaesthesia with propofol and remifentanil without nitrous oxide (FiO2 0.5) was used. Patients were interviewed using a standardized postoperative nausea and vomiting questionnaire at discharge from the post-anaesthesia care unit, 6 h and 24 h later. The severity of nausea was estimated on a 0–100 point numerical scale (0 = no nausea, 100 = maximum nausea). Results: The incidence of vomiting was similar in the esomeprazole (n = 45) and the placebo (n = 48) groups (64.4% vs. 60.5%, P > 0.05). The average nausea score was 17.8 with esomeprazole and was 18.7 with placebo (P > 0.05). Only 24.7% of all patients (esomeprazole 24.4%, placebo 25.0%) did not experience any nausea or vomiting. Conclusion: There is no evidence that prophylactic esomeprazole reduces the incidence of postoperative nausea and vomiting or the degree of postoperative nausea.