BACKGROUND: Postoperative nausea and vomiting is a major challenge in the perioperative setting. The incidence can be as high as 80 percent, and the majority of the symptoms among outpatients occur after discharge. This study evaluated the efficacy of a neurokinin-1 receptor antagonist (aprepitant) in reducing postoperative symptoms for up to 48 hours in patients undergoing outpatient plastic surgery. METHODS: A prospective, double-blinded, randomized, two-arm evaluation of 150 ambulatory plastic surgery patients receiving a standardized general anesthetic, including postoperative nausea and vomiting prophylaxis with ondansetron and either aprepitant or placebo, was performed. The main outcome measures were the occurrence of vomiting and the severity of nausea for up to 48 hours postoperatively. RESULTS: Overall, 9.3 percent of patients who received aprepitant versus 29.7 percent in group B had vomiting, with the majority of vomiting episodes occurring after hospital discharge. The Kaplan-Meier plot of the hazards of vomiting revealed an increased incidence of emesis in patients receiving ondansetron alone compared with the combination of ondansetron and aprepitant (p = 0.006). The incidence of nausea was not significantly different in the two groups. Severity of nausea, however, was significantly higher in those receiving ondansetron alone compared with those receiving ondansetron and aprepitant, as measured by a peak nausea score (p = 0.014) and by multivariate analysis of variance results comparing repeated verbal rating scale scores over 48 hours after surgery (p = 0.024). CONCLUSION: In patients undergoing plastic surgery, the addition of aprepitant to ondansetron significantly decreases postoperative vomiting rates and nausea severity for up to 48 hours postoperatively. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.