Peri-operative prophylactic anti-emetics are commonly used parenterally. Orally disintegrating ondansetron is efficacious during chemotherapy. Therefore, we aimed to study the efficacy of orally disintegrating ondansetron for postoperative nausea and vomiting. In a randomised, double-blind, placebo controlled trial on 109 patients scheduled for laparoscopic cholecystectomy, oral ondansetron was compared to intravenous ondansetron and placebo. The anaesthetic technique was standardised. Mean time (SD) to tolerating oral intake was delayed in the placebo group to 366.1 (77.6) min compared to oral 322.9 (63.7) min and intravenous 322.4 (65.2) min groups. This is corroborated by a higher incidence of nausea and vomiting in the control group during the first 6 h postoperatively (control 44.4%, oral 17.7%, intravenous 18.2%). There was no significant difference between oral and intravenous groups. In conclusion, orally disintegrating ondansetron was as efficacious as intravenous ondansetron in the peri-operative phase and may be a viable option for prophylaxis of emesis in day care surgery.