Chemotherapy-induced nausea and vomiting (CINV) is 1 of the most debilitating side effects of cancer therapy, affecting up to 80% of chemotherapy patients. Chemotherapy drugs are classified according to the associated risk of causing CINV: minimal (less than 10%), low (10% to 30%), moderate (30% to 90%), and high (greater than 90%). High emetogenic chemotherapy (HEC) drugs include a high dose of cisplatin, a high dose of cyclophosphamide (1,500 mg/m or more), and a combination of anthracycline and cyclophosphamide (AC). Moderate emetogenic chemotherapy (MEC) regimens are more variable including carboplatin, oxaliplatin, doxorubicin, and cyclophosphamide. CINV symptoms can manifest at various time points after chemotherapy. There are 3 distinct types of CINV: Acute CINV occurs within 24 hours after administration of chemotherapy, with acute vomiting and nausea, and is primarily mediated by the 5-hydroxytryptamine-3 (5-HT) receptor antagonist. Delayed CINV occurs from 24 hours to 5 days after chemotherapy and is predominantly mediated by the neurokinin 1 (NK) receptor antagonists. Anticipatory CINV occurs before chemotherapy treatment as a conditioned response because of the development of significant CINV from the previous chemotherapy cycles, mediated by both physiologic and psychological mechanisms. The management of CINV has been facilitated from the development of various antiemetic agents with different mechanisms of action. Three most commonly used medications for antiemetic prophylaxis are 5-HT receptor antagonists (5-HT RA), NK RA, and corticosteroids, usually dexamethasone (DEX). Other antiemetic agent such as olanzapine, an atypical antipsychotic, has been used for acute and delayed CINV. These antiemetic agents are used in specific combinations depending on the emetogenicity of the chemotherapy regimen given to different population (i.e., adults or children). Currently available 5-HT RAs for CIVN include ondansetron, granisetron, dolasetron, and palonosetron. The NK RA include aprepitant, fosaprepitant, and rolapitant. On March 14, 2012, Health Canada issued a Notice of Compliance for the IV and oral formulation of palonosetron. IV palonosetron is indicated in adults for “the prevention of acute and delayed nausea and vomiting associated with MEC and the prevention of acute nausea and vomiting associated with HEC, including high dose cisplatin. Oral palonosetron is indicated in adults for the prevention of acute nausea and vomiting associated with MEC”. Palonosetron is a long-lasting, second-generation agent, with higher affinity and binding capacity to 5-HT receptor, and thus has a longer half-life of 40 hours compared to first-generation 5-HT RAs, ondansetron, granisetron, dolasetron, and with a half-life of 3 to 9 hours. Due to its long half-life, palonosetron has been suggested to produce best treatment responses in both acute and delayed CINV of varying emetogenicity. On September 28, 2017, Health Canada issued a Notice of Compliance for netupitant/palonosetron (NEPA) — a combination of a highly selective NK RA netupitant (300 mg) and palonosetron (0.5 mg) — in combination with DEX, for once-per-cycle treatment in adult patients for the “prevention of acute and delayed nausea and vomiting associated with HEC and prevention of acute nausea and vomiting associated with MEC therapy that is uncontrolled by a 5-HT RA.” Over the past decades, the development of new antiemetic drugs has progressed and shown promising results in the prevention of CINV. Particularly, the appearance of second-generation of 5-HT receptor palonosetron and its combination with netupitant in NEPA has urged a literature review on the clinical effectiveness and cost-effectiveness of these drugs relative to other 5-HT RAs. Both dosage forms of palonosetron (IV and oral) were reviewed by the CADTH Common Drug Review in 2012. The combination product palonosetron-netupitant (Akynzeo) was reviewed in 2017. Since then, new evidence and guidelines have emerged on the use of palonosetron as monotherapy or in combination with netupitant to treat adults and children with CINV. The aim of this report is to review the clinical effectiveness and cost-effectiveness of palonosetron for the prevention of CINV in patients receiving HEC or MEC. The report also summarizes the evidence-based guidelines regarding the use of palonosetron for the prevention CINV in patients receiving HEC or MEC.