Patients identified as high risk for postoperative nausea and vomiting (PONV) are often treated prophylactically with intravenous (IV) ondansetron and an additional agent. Limited options exist for a second agent with no adverse effects. The purpose of this investigation was to determine if combining the prophylactic inhalation of isopropyl alcohol (IPA) vapors, an agent with no adverse effects, with IV ondansetron would be more effective than IV ondansetron alone in the prevention of PONV in high-risk patients. A total of 76 patients at high risk for PONV were randomized into control (n = 38) and experimental (n = 38) groups. All patients received IV ondansetron before emergence from general anesthesia. In addition, the experimental group inhaled IPA vapors before induction. Severity of PONV was measured using a 0 to 10 verbal numeric rating scale. Other measured variables included time to onset and incidence of PONV, 24-hour composite nausea score, and satisfaction with nausea control. No significant differences in demographics, surgical or anesthesia time, number of risk factors, severity or incidence of PONV, or satisfaction scores were noted. Prophylactic inhalation of IPA vapors in combination with IV ondansetron was no more efficacious than IV ondansetron alone in the prevention of PONV in a high-risk population.