Purpose: Following laparoscopic surgeries, patients often experience discomfort and dissatisfaction due to postoperative nausea and vomiting (PONV), despite using a multimodal pharmacological approach. The study compared the effects of triple drug prophylaxis with aprepitant-dexamethasone-ondansetron versus dual drug prophylaxis with dexamethasoneondansetron in high-risk patients undergoing laparoscopic surgeries. Methods: This randomized controlled trial enrolled 201 female nonsmokers who used opioids postoperatively and underwent elective laparoscopic surgery. Patients were allocated into two groups: dual prophylactic antiemetics and placebo (control group), and triple prophylactic antiemetics with preoperative administration of aprepitant 80 mg (group A). Group A received oral aprepitant 80 mg 2 hours before the surgery, and the control group received a placebo.Patients were assessed at two time points: 2 hours after surgery, either in the postanesthesia care unit or in the ward, and 24 hours after surgery in the ward. Results: Patients in group A reported a PONV incidence of 10% as compared to 22.7% in the control group (relative risk,0.43; 95% confidence interval [CI], 0.22–0.89; adjusted p = 0.01) at 2 hours in the postoperative period. At 24 hours postoperatively, patients in group A experienced significantly lower incidence of PONV (10%) compared to the control group (29.7%; relative risk, 0.33; 95% CI, 0.17–0.64; p < 0.001). Also, the need for rescue antiemetics was reported to be lower in patients in group A. No adverse effects were reported with any of the drugs used. Conclusion The study suggests that prophylaxis with a triple antiemetic regimen consisting of aprepitant-dexamethasone-ondansetron results in a lower incidence of PONV compared with a two-drug regimen using dexamethasone-ondansetron in high-risk patients with three or more risk factors.