We sought to compare the efficacy of 3 intravenous antiemetic medications in ED patients complaining of moderate to severe nausea. This randomized, placebo-controlled, double-blind trial compares 1.25 mg droperidol, 10 mg metoclopramide, 10 mg prochlorperazine, and saline placebo. Adult ED patients complaining of nausea were eligible. Nausea was measured on a 100-mm visual analog scale at 0 and 30 minutes after treatment. A convenience sample of 100 patients was enrolled; 97 had complete data available for analysis. Of these, 22 patients received droperidol, 25 received metoclopramide, 24 received prochlorperazine, and 26 received placebo. Droperidol (−54.5 mm) was significantly better than metoclopramide (−40.2 mm) or prochlorperazine (−40.5 mm) at reducing nausea at 30 minutes (P = .04). There were no significant differences in rescue medication or patient satisfaction; however, droperidol had significantly higher akathisia (71.4% vs 23.5%) at 24-hour follow-up. When administered intravenously to adult patients with moderate to severe nausea, droperidol was more effective than metoclopramide or prochlorperazine but caused more extrapyramidal symptoms. Metoclopramide and prochlorperazine were not more effective than saline placebo. All patients improved over time and possibly with intravenous hydration.