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Patients with an increased risk of postoperative nausea and vomiting (PONV) are frequently given prophylactic doses of a selective 5-hydroxytryptamine-3 antagonist (5HT3). In chemotherapy patients, it has been demonstrated that after unsuccessful treatment with one 5HT3 administering a different 5HT3 alleviated symptoms. We hypothesized that we could define a benefit of a 5HT3, cross-over in a pilot study of PONV. Two-hundred-fifty female patients received prophylactic ondansetron 4 mg at the end of a surgical procedure requiring general anesthesia and were then followed postoperatively for 4 h.Eighty-eight women developed PONV and were randomly assigned to receive a repeat dose of ondansetron 4 mg (n = 30), granisetron 1 mg (n = 30), or granisetron 0.1 mg (n = 28) and then followed for 24 h.Patients receiving the repeat dose of ondansetron showed a complete response of 57%. Those receiving 1 or 0.1 mg doses of granisetron had rates of 60% and 68%, respectively. This difference was not statistically significant (P = 0.773).Unlike patients with chemotherapy-induced nausea and vomiting, perioperative patients who failed ondansetron prophylaxis did not have a significant response to cross-over dosing with granisetron.