Introduction: Chemotherapy-induced nausea and vomiting (CINV) remain a major barrier to effective cancer care, often impairing quality of life and treatment adherence. While ondansetron has been widely used as a first-generation 5-HT3 receptor antagonist, palonosetron, with a longer half-life, may offer superior protection, particularly in the delayed phase of CINV.

Materials and Methods: This prospective observational study was conducted at Osmania Medical College, Hyderabad, between January 2024 and January 2025. A total of 180 adult patients with histologically confirmed solid tumors receiving moderately or highly emetogenic chemotherapy were included. Patients received either palonosetron (0.25 mg IV) or ondansetron (8 mg IV) along with dexamethasone as per institutional practice.

Results: Complete response over 0–120 h was significantly higher with palonosetron (78.9%) compared to ondansetron (61.1%; p = 0.01). Palonosetron provided superior delayed-phase control (81.1% vs. 64.4%; p = 0.02), reduced nausea (77.8% vs. 60.0%; p = 0.01), and decreased rescue antiemetic use (20.0% vs. 37.8%; p = 0.01). Both drugs had similar safety profiles, with mild headache and constipation being the most common adverse events. Patient satisfaction was higher in the palonosetron group (57.8% delighted vs. 38.9%; p = 0.03).

Conclusion: Palonosetron was more effective than ondansetron, particularly in the delayed phase, while maintaining comparable safety. Its use may improve patient satisfaction and adherence to chemotherapy.