OBJECTIVES: The authors sought to compare ondansetron and promethazine among emergency department (ED) patients with undifferentiated nausea. The hypothesis was that ondansetron was not inferior to promethazine and that rates of adverse effects were similar. METHODS: This was a randomized double-blind noninferiority clinical trial conducted in an urban academic ED. A convenience sample of nonpregnant adults with at least 40 mm of self-reported nausea measured on a 100-mm visual analog scale (VAS) were enrolled. Patients who had already received more than 1 L of intravenous fluid or an antiemetic agent were excluded. Subjects were block-randomized in groups of 10 to either 4 mg of ondansetron or 25 mg of promethazine delivered intravenously. The primary outcome was change in nausea over 30 minutes. The authors used a 15-mm margin of noninferiority. Secondary endpoints included changes in anxiety, sedation, and other adverse effects. Analyses included t-tests, tests for proportions, and 95% confidence intervals (CIs). RESULTS: A total of 120 subjects completed the study, 60 in each arm. Baseline nausea, anxiety, and sedation scores were similar. Ondansetron and promethazine reduced nausea similarly (ondansetron -34 mm, promethazine -36 mm; difference -2 mm; 95% CI = -13 to 8 mm). The reduction in anxiety was similar (ondansetron -13 mm, promethazine -14 mm; difference -1 mm; 95% CI = -10 to 10 mm). Promethazine was associated with significantly more sedation than ondansetron (ondansetron 5 mm, promethazine 19 mm; difference 14 mm; 95% CI = 5 to 24 mm). There were no cases of akathisia in the ondansetron group and 2 cases in the promethazine group. CONCLUSIONS: Promethazine and ondansetron have similar efficacy in reducing nausea among ED patients. Change in anxiety was similar, but promethazine was associated with greater sedation.