Background. Ondansetron is a serotonin antagonist that recently has been introduced as a preventive agent for chemotherapy-induced nausea and vomiting. The current study was performed to determine the degree of antiemetic control of ondansetron in combination with dexamethasone and lorazepam, and to compare this combination to the previously very effective regimen of lorazepam, dexamethasone, diphenhydramine, and continuous-infusion metoclopramide. Methods. Eighty chemotherapy-naive patients with newly diagnosed neoplasms undergoing cisplatin combination chemotherapy were randomized to receive one of two combination antiemetic regimens: lorazepam, dexamethasone, intermittent intravenous ondansetron; or lorazepam, dexamethasone, continuous-infusion metoclopramide, and diphenhydramine. Results. There was major control (0-1 episodes) of acute nausea-vomiting in all of the patients receiving the ondansetron combination antiemetic regimen, which was significantly better (P < 0.05) than the major control of the acute nausea-vomiting of the patients receiving the metoclopramide combination antiemetic regimen. The ondansetron-treated patients experienced only a mild headache as their only toxicity and had significantly (P 0.0026) less diarrhea, akathisia, and acute dystonic reactions than the patients receiving the metoclopramide regimen. Delayed nausea was controlled with prophylactic prochlorperazine. Conclusions. The ondansetron regimen was more effective and less toxic, but its cost was 20 times more than the metoclopramide regimen.