BACKGROUND: Postoperative nausea and vomiting (PONV) is one of the major concerns after anesthesia and surgery, and it may be more frequent in orthopedic patients receiving patient-controlled epidural analgesia (PCEA). The purpose of this study was to compare the effect of palonosetron and dexamethasone on the prevention of PONV in patients undergoing total joint arthroplasty and receiving PCEA. METHODS: Patients scheduled for total hip or knee arthroplasty under spinal anesthesia/PCEA were randomly allocated to receive either intravenous palonosetron (0.075 mg, n = 50) or dexamethasone (5 mg, n = 50). Treatments were administered intravenously to the patients 30 min before the beginning of surgery. The total incidence of PONV and incidence in each time period, severity of nausea, need for rescue anti-emetics, pain score, and adverse effects during the first 48 h postoperatively were evaluated. RESULTS: The total incidence of PONV was lower in the palonosetron group compared with the dexamethasone group (18.4% vs. 36.7%, P = 0.042), but there were no statistically significant differences in incidence between the groups at all time points. No significant intergroup differences were observed in the severity of nausea, use of rescue anti-emetics, pain score, and adverse effects. CONCLUSIONS: Although there were no significant differences in the incidence of PONV between the treatment groups at all time points, intravenous palonosetron reduced the total incidence of PONV in orthopedic patients receiving PCEA compared with dexamethasone.