BACKGROUND: Thyroidectomy has been a surgical procedure associated with a high incidence of postoperative nausea and vomiting (PONV), and conventional antiemetics cannot prevent PONV effectively. In this study, we compared the efficacy and safety of ondansetron 70 microgram/kg, droperidol 10 microgram/kg and combination of both drugs to placebo in the prevention of PONV. METHODS: Seventy-six patients undergoing thyroidectomy were randomized to receive placebo (Group I, n=20), ondansetron 70 microgram/kg (Group II, n=19), droperidol 10 microgram/kg (Group III, n=18) and combination of both drugs (Group IV, n=19). The effects of these regimens on the incidence and severity of PONV and adverse events were analyzed for the 0 to 1 hour and 1 to 24 hours postoperative periods. RESULTS: In the 0 to 1 hour postoperative periods, the incidence of symptom free (no nausea and retching or vomiting) paients were 60% for placebo, 68.4% for ondansetron (p>0.05 versus placebo group), 88.9% for droperidol (p<0.05 versus placebo group), and 94.7% for combination of both drugs (p<0.05 versus placebo and ondansetron group). In the 1 to 24 hours postoperative period, the incidence of symptom free patients were 35% for placebo, 52.6% for ondansetron (p>0.05 versus placebo group), 77.8% for droperidol (p<0.05 versus placebo group), and 78.9% for combination of both drugs (p<0.05 versus placebo group). Overall, during the first 24 hours postoperatively, the incidence of symptom free patients were 30% for placebo, 42.1% for ondansetron (p>0.05 versus placebo group), 77.8% for droperidol (p<0.05 versus placebo and ondansetron group), and 73.7% for combination of both drugs (p<0.05 versus placebo and ondansetron group). Also, there were no significant differences between the droperidol and droperidol plus ondansetron group. Among the side effects associated with antiemetics, headache and dizziness incidence was higher. CONCLUSIONS: Droperidol and combination of ondansetron plus droperidol was superior to placebo, and ondansetron for prevention of PONV during the first 24 hours postoperative period.