Background/Aim: To evaluate the efficacy of palonosetron in preventing acute and delayed nausea and vomiting in patients receiving highly emetogenic chemotherapy (HEC) in oral cancer patients. Patients and Methods: Oral cancer patients receiving HEC were enrolled; among the 40 patients, 87 courses of chemotherapy were administered. On day 1, 0.75 mg palonosetron was intravenously administrated just before chemotherapy. Results: The primary endpoint was the proportion of patients with a complete response (CR) and the secondary endpoint was the proportion of patients with complete control (CC) during the acute and delayed phase. During the acute phase, 86 of 87 courses (98.9%) had CR and 84 of 87 courses (96.6%) had CC. During the delayed phase, 84 of 87 courses (96.6%) had CR and 70 of 87 courses (80.5%) had CC. Conclusion: Palonosetron is effective at preventing HEC-induced chemotherapy-induced nausea and vomiting (CINV) in oral cancer chemotherapeutic regimens in the acute and delayed phases.