Postoperative nausea and vomiting is a frequent complication of craniotomy. We evaluated the ability of intraoperative IV ondansetron followed by postoperative ondansetron in an orally disintegrating tablet formulation to reduce the frequency and severity of postoperative nausea and vomiting in a prospective, randomized, placebo-controlled double-blind trial of 60 patients undergoing acoustic neuroma resection. Each patient received intraoperative ondansetron (4 mg IV) or placebo 30 min before case end. Postoperatively, patients received ondansetron in an orally disintegrating tablet formulation (8 mg BID) or placebo twice a day for up to 72 h. Metoclopramide was available as rescue therapy for both groups. Severity of nausea (as measured on a 10-cm visual scale), number of emetic episodes, and requirement for rescue therapy were recorded. In the immediate postoperative period, nausea severity was less in patients treated with ondansetron than placebo (3.3 +/- 4.1 versus 7.3 +/- 4.2; P < 0.001) and fewer patients experienced vomiting (3 of 28 versus 11 of 32; chi2 P < 0.01). More patients required some form of rescue treatment in the placebo group on the first postoperative day (26 of 32 versus 16 of 28; chi2 P < 0.01). We conclude that after acoustic neuroma surgery IV ondansetron treatment prevents immediate postoperative nausea and vomiting. Postoperative treatment with ondansetron in an orally disintegrating tablet formulation was associated with less frequent rescue therapy as compared with placebo on the first postoperative day.