Purpose: To compare the antiemetic efficacy of a single dose of an oral antiemetic (granisetron 2 mg) with a single dose of an intravenous (IV) antiemetic (ondansetron 32 mg) given before cisplatin-based chemotherapy. Patients and Methods: This was a multicenter, randomized, double-blind, parallel-group study. Patients (N = 1,054) scheduled to receive cisplatin (≤ 60 mg/m2)-based chemotherapy were randomized to receive either 2 mg of oral granisetron tablets 1 hour before chemotherapy (n = 534) or IV ondansetron (32 mg) 30 minutes before chemotherapy (n = 520). The primary efficacy end point was total control (no emesis, no nausea, and no use of antiemetic rescue medication) over the initial 24 hours after the start of chemotherapy. Dexamethasone or methylprednisolone were permitted, but not required, as concomitant prophylactic antiemetics. Results: Total control was equivalent 24 hours after cisplatin chemotherapy for single-dose oral granisetron (54.7%) and IV ondansetron (58.3%) (95% confidence interval [CI], - 9.6 to 2.4). Similar proportions of patients remained nausea-free in the granisetron group (55.4%) and the ondansetron group (59%) (95% CI, - 9.6 to 2.4). The rate of complete control of emesis was 61.2% in the granisetron group and 67.1% in the ondansetron group (95% CI, - 11.7 to - 0.1). Both treatment regimens were well tolerated, with similar patterns of adverse reactions, generally of a mild degree. The most common side effects included constipation (14%), headache (15%), and diarrhea (10%). Conclusion: Oral granisetron, administered as a single 2-mg dose, provided equivalent total antiemetic control when compared with IV ondansetron (32 mg) in patients who received highly emetogenic, cisplatin-based chemotherapy.