SummaryWe compared the prophylactic anti-emetic efficacy of ramosetron, a newly developed 5-HT 3 antagonist, and ondansetron in patients at high-risk for postoperative nausea and vomiting after total knee replacement. Eighty-four patients with three risk factors for postoperative nausea and vomiting (female, non-smoking and use of postoperative opioid use (ropivacaine and hydromorphone patient controlled epidural analgesia)) undergoing unilateral total knee replacement were randomly allocated to ramosetron 0.3 mg (n = 42) or ondansetron 4 mg (n = 42) groups. A complete response (no postoperative nausea and vomiting and no rescue anti-emetic) and the incidence of postoperative nausea and vomiting were assessed for 48 h after surgery at 0-2 h, 2-6 h, 6-24 h, and 24-48 h. More patients in the ramosetron group had a complete response between 2 and 48 h. The incidence of nausea between 2 and 24 h and the severity of nausea between 2 and 48 h were also less in the ramosetron group. Ramosetron was more effective than ondansetron in preventing postoperative nausea and vomiting in patients at high risk undergoing unilateral total knee replacement.