Background: Chemotherapy induced nausea and vomiting (CINV) is considered the main fear for both oncologists and patients. It affects quality of life dramatically, especially the food intake and nutritional status. This can be clearly observed in highly emetogenic chemotherapy (HEC) such as AC protocol in breast cancer patients or cisplatin based regimens in other types of cancer. Objectives: The aim of this study was to evaluate the antiemetic efficacy of palonosetron (palono) over granisetron (grani) in combination dexamethasone for multiple high emetogenic risk (HER) anticancer agents especially in chemotherapy regimens in breast cancer and Cisplatin based regimens. Methods: We carried out an open-label randomized trial including 115 patients receiving at least 4 courses of highly emetogenic chemotherapy regimens. All patients received dexamethasone in combination with the 5-HT3 receptor antagonist. Clinical and biochemical characteristics of patients were recorded, and blood samples were drawn to monitor serum substance P and serotonin in correlation with chemotherapy induced nausea and vomiting (CINV). Besides, (MASCC) antiemetic tool in acute phase (0hr-24hr) and delayed phase (24hr-120hr) was used to evaluate patient`s outcomes in both phases after each chemotherapy cycle. Results: In palono group, only 5% of patients showed acute nausea and vomiting, whereas 29.3% of patients showed acute vomiting and 74.6% showed acute nausea in grani group (p<0.0001). For delayed CINV, 5.8% of patients showed delayed vomiting and 24.5% showed delayed nausea in palono group, while 69.5 % patients showed delayed emesis and 91.4 % patients showed delayed nausea in grani group (p<0.0001). Adverse events of both antiemetic drugs (palono and grani) were mostly mild to moderate, with quite low rates among the two groups. Conclusion: Palonosetron in combination with dexamethasone is more effective granisetron and dexamethasone combination against both acute and delayed emesis induced by highly emetogenic cisplatin-based chemotherapy and highly emetogenic combination of cyclophosphamide and anthracyclines (AC).