The study investigated the optimal dosing regimen of oral soluble ondansetron pellets for the prevention of postoperative nausea and vomiting (PONV) after primary total joint arthroplasty in 198 patients. Patients were divided into three groups with different doses: (1) 16 mg preoperatively and 16 mg 6 hours postoperatively, (2) 16 mg preoperatively and 8 mg 6 hours postoperatively, (3) 8 mg preoperatively, 8 mg 6 hours, and 8 mg 12 hours postoperatively. The results showed that the groups with 16 mg doses before surgery (groups 1 and 2) had a significantly lower incidence of postoperative nausea compared to the group with three 8 mg doses. There were no statistically significant differences in the severity of PONV or frequency of vomiting between groups. The 16 + 8 mg regimen group also had a significantly lower need for rescue metoclopramide treatment than the three 8 mg dose group. Tramadol use and incidence of adverse events did not differ between groups. Therefore, the 16 + 8 mg regimen appears to be optimal for the prevention of PONV in patients after total joint arthroplasty, especially in high-risk patients.