This prospective, double-blind, randomized study compares the antiemetic efficacy of an equivalent dose of ondansetron administered as a single high dose or as multiple standard doses in pediatric oncology patients. Thirty-one chemotherapy-naive patients were randomized at diagnosis to receive either single high-dose ondansetron (0.6 mg/kg, maximum dose 32 mg) or multiple standard-dose ondansetron (0.15 mg/kg, maximum dose 8 mg, every 4 hr for four doses). Antiemetic efficacy was assessed by an emesis scale described as follows: 1, no nausea or emesis; 2, nauseous but able to eat; 3, nauseous and unable to eat; and 4, emesis. Sixteen patients received high-dose and 15 received standard-dose ondansetron. Patients receiving moderately or severely emetogenic chemotherapy were evenly distributed between the two treatment groups. Eighty-one percent of patients receiving high-dose and 80% receiving standard-dose ondansetron rated 1 or 2 on the emesis scale (p = 0.93). No patient experienced any clinical or laboratory toxicity. Our study suggests that single high-dose ondansetron is as efficacious as the multiple standard-dose regimen and is well tolerated. Its use will facilitate the administration of ondansetron in pediatric patients receiving chemotherapy.