Purpose: To assess the comparative antiemetic efficacy of single-dose intravenous (IV) dolasetron mesylate and ondansetron in preventing cisplatin-induced nausea and vomiting. Patients and Methods: Cancer patients (n = 609) receiving first-course cisplatin chemotherapy were randomized to one of three treatments: 1.8 or 2.4 mg/kg dolasetron mesylate salt (equivalent to 1.3 and 1.8 mg/kg dolasetron base, respectively) or 32 mg ondansetron. Each treatment was infused over 15 minutes, 30 minutes before cisplatin administration. Patients were stratified to cisplatin doses of ≤ 70 and less than 91 mg/m2 (n = 368) or ≤ 91 mg/m2 (n = 241), administered over ≤ 3 hours. Protocol-defined efficacy criteria included complete response (zero emetic episodes and no rescue medication), major response (1 to 2 emetic episodes and no rescue medication), and patients' report of nausea severity and satisfaction recorded on a 100-mm visual analog scale (VAS). Results: The three treatments met protocol-specified criteria for equivalence. Complete response rates for dolasetron mesylate 1.8 mg/kg, 2.4 mg/kg, and ondansetron, respectively, were 49.2%, 45.6%, and 50.4% for patients in the lower cisplatin stratum (mean, 74.7 mg/m2) and 36.8%, 31.3%, and 31.8% in the higher cisplatin stratum (mean, 100.6 mg/m2). No significant differences were observed in the extent of nausea with either dolasetron dose compared with ondansetron. Less nausea was noted with 1.8 mg/kg dolasetron compared with the 2.4 mg/kg dose (P = .044). All three antiemetic treatments were well tolerated. Asymptomatic electrocardiogram changes were recorded with bath dolasetron and ondansetron. Conclusion: A single IV dose of dolasetron mesylate (1.8 or 2.4 mg/kg) has comparable safety and efficacy to a single 32-mg IV dose of ondansetron in patients receiving cisplatin chemotherapy.