UNLABELLED: Nausea or vomiting occurs frequently after craniotomy. Because of the need for frequent postoperative neurological assessment, an effective antiemetic with minimal sedative side effects is needed. Therefore, we compared ondansetron to droperidol in a randomized, double-blinded, placebo-controlled study. A total of 60 adults requiring elective supratentorial craniotomy received standardized IV anesthesia with 4 mg of ondansetron, 0.625 mg of droperidol, or placebo at skin closure. The incidence of postoperative nausea, emesis, pain and sedation scores, and rescue antiemetic use were recorded at 0, 0.5, 1, 4, 8, 12, 24, and 48 h. All groups were demographically similar. Differences existed for cumulative 8, 12, and 24 h incidences of nausea (24 h, P = 0.03) and emesis (24 h, P = 0.04). Within 4 h, when maximal effect could be expected from treatment, 20% of the ondansetron group, 25% of the droperidol group and 50% of the placebo group received rescue antiemetic (P = 0.12). No differences in pain (P = 0.82) or sedation (P = 0.74) scores were detected. Both ondansetron and droperidol prevent nausea; however, only droperidol reduces emesis after supratentorial craniotomy. The dose of droperidol used was not more sedating than ondansetron. Sustained reduction in nausea and emesis over 24 h indicates a preemptive benefit of prophylactic antiemetic in this surgical population. IMPLICATIONS: Nausea and vomiting after brain surgery are particularly troubling, because effective treatment may cause sedation, making postoperative neurological assessment difficult. Our study shows that both ondansetron and droperidol are effective in reducing nausea, and that droperidol is particularly effective in reducing vomiting. Neither drug caused more sedation than placebo.