To compare ondansetron (GR 38032F), a 5-hydroxytryptamine3-receptor antagonist, with metoclopramide in the prophylaxis of acute cisplatin-induced emesis, we conducted a double-blind crossover study in 97 patients scheduled to receive cisplatin (80 to 100 mg per square meter of body-surface area) for treatment of cancer. None had received chemotherapy before this trial. Among the 76 patients who satisfactorily completed both parts of the study, complete or nearly complete control of emesis (i.e., no episodes of emesis occurred, or only one or two) was achieved in 57 of 76 treatments (75 percent) with ondansetron and in 32 of 76 treatments (42 percent) with metoclopramide (P less than 0.001). Ondansetron was also more effective in controlling acute nausea, as assessed with a visual-analogue scale (P = 0.019) or a graded scale (P = 0.024). There was a significant preference among patients for ondansetron (55 vs. 26 percent; P = 0.006). Dystonic reactions were observed during three treatments with metoclopramide; both agents were otherwise well tolerated. We conclude that ondansetron is more effective than metoclopramide in the control of cisplatin-induced nausea and vomiting, and that this suggests that serotonin is an important mediator of this side effect.