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In this prospective, multicenter, observational study, we evaluated the incidence and time course of postoperative nausea and vomiting (PONV), assessed prophylactic and rescue antiemetic use in high-risk patients, and determined population-based effectiveness of antiemetics, including the impact of American Society of Anesthesiologists (ASA) and American Society of Perianesthesia Nurses (ASPAN) guideline compliance.Eligible patients undergoing elective laparoscopic or major plastic surgery possessed two or more of the following Apfel PONV risk factors: female gender, history of PONV or motion sickness, and nonsmoking status. Antiemetic use, emetic episodes, severity of nausea, and functional interference due to PONV were documented during the first 72 h after surgery. Complete response (CR) was defined as no emesis or rescue medication use, and complete control was defined as CR and no moderate-severe nausea. The effect of compliance (versus noncompliance) with ASA and ASPAN guidelines on PONV outcomes was also analyzed.The proportion of patients experiencing postoperative emesis ranged from 18% to 40% depending on the number of antiemetics administered. The rate of rescue medication (45%) was similar to the reported incidences of moderate-to-severe nausea (47%) and functional interference due to emetic symptoms (44%). The administration of three or more antiemetics produced better patient outcomes overall compared to <1 prophylactic antiemetic. CR rates were <70% despite adherence to current organizational PONV management guidelines (ASA: 69%; ASPAN: 63%). The complete control rates were 10% lower than CR rates over the 3 day study period.Administration of three or more prophylactic antiemetics had the most positive impact on emetic outcomes over 72 hrs in patients at risk of developing PONV. Although compliance with organizational PONV management guidelines improved patient outcomes, postoperative emetic symptoms and interference with patient functioning still occurred in more than 30% of these high-risk patients.